Methods for Forming Protected Organoboronic Acids

ABSTRACT

Described are methods of forming protected boronic acids that provide in a manner that is straightforward, scalable, and cost-effective a wide variety of building blocks, such as building blocks containing complex and/or pharmaceutically important structures, and/or provide simple or complex protected organoboronic acid building blocks. A first method includes reacting an imino-di-carboxylic acid and an organoboronate salt. A second method includes reacting a N-substituted morpholine dione and an organoboronic acid.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 61/305,603, filed Feb. 18, 2010.

GOVERNMENT SUPPORT

The subject matter of this application may have been funded in partunder a research grant from the National Science Foundation under GrantNumber Career 0747778, and under a research grant from the NationalInstitutes of Health under Chemical Biology Interface Training Number1-492576-510000-191788. The U.S. Government may have rights in thisinvention.

BACKGROUND

The Suzuki-Miyaura reaction is a palladium- or nickel-catalyzed crosscoupling between a boronic acid or a boronic ester, and an organohalideor an organo-pseudohalide. (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,2457-2483) This cross coupling transformation is a powerful method forC—C bond formation in complex molecule synthesis. The reaction istolerant of functional groups, and has become increasingly general andwidespread in its use for coupling of organic compounds. (Barder, T. E.;Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4685-4696; Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc.2007, 129, 3358-3366; Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem.Soc. 2000, 122, 4020-4028.; Nicolaou, K. C., et al. Angew. Chem. Int.Ed. 2005, 44, 4442) A difficult aspect of the Suzuki-Miyaura reaction isthe sensitivity of the boronic acid functional group to many commonreagent, which makes the synthesis of structurally complex organoboronicacid building blocks challenging. (Hall, D. G. Boronic Acids, Wiley-VCH,Germany, 2005, 3-14.; Tyrell, 2003)

One area of research on the Suzuki-Miyaura reaction is the developmentof protecting groups for the boronic acid functional group. In oneexample of a boronic acid protecting group, each of the two B—OH groupsis converted into a boronic ester group (>B—O—R) or a boronic amidegroup (>B—NH—R), where R is an organic group. (Deng, X.; Mayeux, A.;Cai, C. J. Org. Chem. 2002, 67, 5279-5283; Hohn, E.; Pietruszka, J. Adv.Synth. Catal. 2004, 346, 863-866; Holmes, D., et al. Org. Lett. 2006, 8,1407-1410; Noguchi, H.; Hojo, K.; Suginome, M. J. Am. Chem. Soc. 2007,129, 758-759) The heteroatom—boron bonds in these protected compoundstend to be very strong, however, and the relatively harsh conditionsrequired for cleaving these ligands to provide the free boronic acidgroup typically are incompatible with complex molecule synthesis. Inanother example, three organoboronic acid molecules can be condensed toform a cyclic boroxine protecting group. (Kerins, F.; O'Shea, D. F. J.Org. Chem. 2002, 67, 4968-4971) These protected organoboronic acids,however, tend to be unstable to long term storage. The reactivity of aboronic acid group also may be decreased by conversion of the boronicacid group into a tetracoordinate anion, such as [R—BF₃]⁻, where Rrepresents an organic group, as a salt with a counterion such as K⁺ orNa⁺. (Molander, G. A; Ellis, N. Acc. Chem. Res. 2007, 40, 275-286)Another class of tetracoordinate boron anions, [R—B(OH)₃]⁻, has beenreported in the context of purifying organoboronic acids for use in theSuzuki-Miyaura reaction. (Cammidge, A. N. et al. Organic Letters 2006,8, 4071-4074) In each of these systems, the boron itself is notprotected from the Suzuki-Miyaura reaction, but can be used directly inthe coupling transformation.

The most useful and versatile system for protecting boronic acids is theuse of an imino-di-carboxylic acid boronate protecting group.Imino-di-carboxylic acid boronates, such as N-methyliminodiacetic acid(MIDA), can be used to protect boronic acid functional groups from avariety of chemical reactions. (U.S. Pat. App. Pub. 2009/0030238;Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716-6717; Lee,S. J., Gray, K. C., Paek, J. S., Burke, M. D. J. Am. Chem. Soc. 2008,130, 466-468) The MIDA boronates are stable to air and to purificationby chromatography, and do not cross-couple under anhydrous conditions.However, the protecting group can be hydrolyzed with aqueous base torelease the corresponding unprotected organoboronic acid. Thus, MIDAboronates can be used as convenient surrogates for organoboronic acidsunder aqueous base-promoted Suzuki-Miyaura coupling conditions, and thedeprotection and cross-coupling may be performed as a single step in thepresence of aqueous base. This approach has been shown to be effectivefor a wide variety of organoboronic acids.

The base used to simultaneously deprotect the MIDA boronate and promotethe cross-coupling reaction may be a mild base. Deprotection of MIDAboronates with a mild base can provide a slower release of theunprotected organoboronic acid into the reaction mixture than thatprovided through deprotection with a strong base. This slower releasecan allow cross-coupling to occur between an organohalide or anorgano-pseudohalide and an organoboronic acid that would otherwisedegrade during the reaction. This slower release also can allowcross-coupling to occur with organoboronic acids that cannot be preparedor isolated in pure form. The method of deprotecting and cross-couplingwith a mild base is described, for example, in copending U.S. patentapplication Ser. No. 12/567,443, entitled “Slow Release of OrganoboronicAcids In Cross-Coupling Reactions”, with inventors Martin D. Burke etal., which is incorporated herein by reference.

A challenge that remains in the MIDA protecting system is the formationof protected organoboronic acid building blocks for use in synthesis ofcomplex organic compounds. It would be desirable to provide a widevariety of building blocks, and particularly to provide building blockscontaining complex and/or pharmaceutically important structures. It alsowould be desirable to provide a method of forming simple or complexprotected organoboronic acid building blocks that is morestraightforward, scalable, and cost-effective.

Regarding the formation of building blocks containing complex and/orpharmaceutically important structures, one such class of structures isthe 2-heterocyclic groups. Many pharmaceuticals contain 2-heterocyclicsubunits, with 2-pyridyl, 2-furan, 2-thiophene, 2-indole, 2-oxazole, and2-thiazole being among the most common. These same substructures arealso prevalent in natural products, particularly those derived from NRPSand hybrid PKS/NRPS biosynthesis pathways. 2-Substituted heterocyclesalso commonly appear in probe reagents for chemical biological studies,metal-complexing ligands, and a variety of materials for molecularelectronic, display, energy capture, energy storage, and field effecttransistor devices.

Although they are among the most desirable synthetic building blockswith respect to low cost, minimal environmental impact, and lack oftoxicity, 2-heterocyclic boronic acids are notoriously unstable, whichoften precludes their effective utilization. Many different types ofsurrogates have been developed, including trifluoroborate salts,trialkoxy or trihydroxyborate salts, diethanolamine adducts, stericallybulky boronic esters and boroxines. Advances in the development of2-heterocyclic silanolates have also recently been reported. However, itremains a challenge to develop air-stable, chemically pure, and highlyeffective surrogates for some of the most challenging classes of2-heterocyclic building blocks, e.g., the notoriously unstable 2-pyridylderivatives. 2-heterocyclic stannanes represent stable and effectivealternatives, but these reagents suffer from substantial toxicity.

A variety of 2-heterocyclic MIDA boronates have been used successfullyin cross-coupling reactions. (U.S. patent application Ser. No.12/567,443) The 2-heterocyclic MIDA boronate building blocks were notformed by reaction of MIDA with the corresponding unprotected boronicacids, however, as the unprotected boronic acids are notoriouslyunstable. While alternative methods have been used to form MIDAboronates of boronic acids that would be unstable if unprotected, thesemethods have met with mixed success. In particular, formation of2-heterocyclic MIDA boronates containing nitrogen at the 2-position inthe heterocyclic group have been cumbersome and low yielding, and havenot shown characteristics of scalability. For example, the formation of2-pyridyl MIDA boronate by reaction of lithium2-pyridyl-triisopropylboronate with MIDA in DMSO at 75° C. provided onlya 27% yield. Thus, it would be desirable to provide an improved methodfor forming MIDA boronates containing complex and/or pharmaceuticallyimportant structures.

Regarding the formation of simple or complex protected organoboronicacid building blocks in a manner that is more straightforward, scalable,and cost-effective, many MIDA boronates can be prepared by refluxing amixture of the corresponding boronic acid and MIDA in toluene and DMSOin a Dean-Stark apparatus. The DMSO conventionally has been required topartially dissolve the highly polar MIDA reagent. Refluxing in aDean-Stark apparatus conventionally has been necessary to remove thewater that is generated during the complexation process. Thisconventional method presents a number of challenges, however. Someboronic acids can undergo thermal decomposition at the elevatedtemperatures of refluxing DMSO, resulting in decreased yields of theMIDA boronate. Moreover, the MIDA reagent can cause the reactionconditions to be acidic, which can be detrimental to acid-sensitiveboronic acids. Finally, the DMSO used in the reaction can be challengingto completely remove from the MIDA boronate product.

For example, in the preparation of 5-bromopentanyl MIDA boronate from5-bromopentanyl boronic acid using the conventional Dean-Starkconditions (PhMe:DMSO 10:1), the 5-bromopentanyl boronic acidsubstantially decomposed, resulting in low yields of 5-bromopentanylMIDA boronate. Moreover, the reaction product included residual DMSO,which was difficult to remove.

The number of commercially available boronic acids currently is over3,000. Moreover, methods for making many other boronic acids arewell-known. Thus, it would be desirable to provide a simple andefficient process to transform directly any boronic acid into thecorresponding MIDA boronate.

SUMMARY

In one aspect, the invention provides a method of forming a protectedboronic acid, which includes reacting in a reaction mixture animino-di-carboxylic acid and an organoboronate salt represented byformula (I):

[R¹—B(OR²)(OR³)(OR⁴)]⁻M⁺  (I),

where R¹ represents an organic group; R², R³ and R⁴ independently are analkyl group or an aryl group; and M⁺ is a metal ion, a metal halide ionor an ammonium ion. The reaction mixture further includes a polaraprotic solvent, and the reacting includes maintaining the reactionmixture at a temperature of at least 100° C. The method further includesforming a protected organoboronic acid represented by formula (III) inthe reaction mixture:

where R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently are a hydrogen group oran organic group.

In another aspect, the invention provides a method of forming aprotected boronic acid, which includes reacting in a reaction mixture aN-substituted morpholine dione and an organoboronic acid represented byformula (XII):

R¹—B(OH)₂  (XII),

where R¹ represents an organic group. The reaction mixture furtherincludes a polar aprotic solvent. The method further includes forming aprotected organoboronic acid represented by formula (III) in thereaction mixture:

where R¹⁰ represents an organic group; and R¹¹, R¹², R¹³ and R¹⁴independently are a hydrogen group or an organic group.

The following definitions are included to provide a clear and consistentunderstanding of the specification and claims.

The term “organoboronic acid” means a compound represented by formula(XII):

R¹—B(OH)₂  (XII),

where R¹ is an organic group that is bonded to the boron through aboron-carbon bond.

The term “group” means a linked collection of atoms or a single atomwithin a molecular entity, where a molecular entity is anyconstitutionally or isotopically distinct atom, molecule, ion, ion pair,radical, radical ion, complex, conformer etc., identifiable as aseparately distinguishable entity. The description of a group as being“formed by” a particular chemical transformation does not imply thatthis chemical transformation is involved in making the molecular entitythat includes the group.

The term “organic group” means a group containing at least one carbonatom.

The term “protected organoboronic acid” means a chemical transform of anorganoboronic acid, in which the boron has a lower chemical reactivityrelative to the original organoboronic acid.

The term “chemical transform” of a substance means a product of achemical transformation of the substance, where the product has achemical structure different from that of the substance. A chemicaltransform of a substance may or may not actually be formed from thesubstance.

The term “chemical transformation” means the conversion of a substanceinto a product, irrespective of reagents or mechanisms involved.

The term “sp³ hybridization” means that an atom is bonded and/orcoordinated in a configuration having a tetrahedral character of atleast 50%. For tetracoordinate boron atoms, the tetrahedral character ofthe boron atom is calculated by the method of Hopfl, H., J. Organomet.Chem. 1999, 581, 129-149. In this method, the tetrahedral character isdefined as:

THC _(DA)[%]=100×[1−(Σ_(n=1-6)|109.5−θ_(n)|°/90°)]

where θ_(n) is one of the six bond angles of the boron atom.

The term “protecting group” means an organic group bonded to at leastone atom, where the atom has a lower chemical activity than when it isnot bonded to the protecting group. For boron containing compounds, theterm excludes non-organic groups used to lower the chemical activity ofthe boron, such as the F⁻ and OH⁻ ligands of —BF₃ ⁻ and —B(OH)₃ ⁻.

The term “conformationally rigid protecting group” means an organicprotecting group that, when bonded to a boron atom, is determined to beconformationally rigid by the “conformational rigidity test”.

The term “alkyl group” means a group formed by removing a hydrogen froma carbon of an alkane, where an alkane is an acyclic or cyclic compoundconsisting entirely of hydrogen atoms and saturated carbon atoms. Analkyl group may include one or more substituent groups.

The term “heteroalkyl group” means a group formed by removing a hydrogenfrom a carbon of a heteroalkane, where a heteroalkane is an acyclic orcyclic compound consisting entirely of hydrogen atoms, saturated carbonatoms, and one or more heteroatoms. A heteroalkyl group may include oneor more substituent groups.

The term “alkenyl group” means a group formed by removing a hydrogenfrom a carbon of an alkene, where an alkene is an acyclic or cycliccompound consisting entirely of hydrogen atoms and carbon atoms, andincluding at least one carbon-carbon double bond. An alkenyl group mayinclude one or more substituent groups.

The term “heteroalkenyl group” means a group formed by removing ahydrogen from a carbon of a heteroalkene, where a heteroalkene is anacyclic or cyclic compound consisting entirely of hydrogen atoms, carbonatoms and one or more heteroatoms, and including at least onecarbon-carbon double bond. A heteroalkenyl group may include one or moresubstituent groups.

The term “alkynyl group” means a group formed by removing a hydrogenfrom a carbon of an alkyne, where an alkyne is an acyclic or cycliccompound consisting entirely of hydrogen atoms and carbon atoms, andincluding at least one carbon-carbon triple bond. An alkynyl group mayinclude one or more substituent groups.

The term “heteroalkynyl group” means a group formed by removing ahydrogen from a carbon of a heteroalkyne, where a heteroalkyne is anacyclic or cyclic compound consisting entirely of hydrogen atoms, carbonatoms and one or more heteroatoms, and including at least onecarbon-carbon triple bond. A heteroalkynyl group may include one or moresubstituent groups.

The term “aryl group” means a group formed by removing a hydrogen from aring carbon atom of an aromatic hydrocarbon. An aryl group may bymonocyclic or polycyclic and may include one or more substituent groups.

The term “heteroaryl group” means a group formed by replacing one ormore methine (—C═) and/or vinylene (—CH═CH—) groups in an aryl groupwith a trivalent or divalent heteroatom, respectively. A heteroarylgroup may by monocyclic or polycyclic and may include one or moresubstituent groups.

The term “heterocyclic group” means a group formed by removing ahydrogen from a carbon of a heterocycle, where a heterocycle is a cycliccompound consisting entirely of hydrogen atoms, saturated carbon atoms,and one or more heteroatoms. A heterocyclic group may include one ormore substituent groups. Heterocyclic groups include cyclic heteroalkylgroups, cyclic heteroalkenyl groups, cyclic heteroalkynyl groups andheteroaryl groups. A 2-heterocyclic groups is a heterocyclic groupcontaining a heteroatom at the 2-position in the ring.

The term “substituent group” means a group that replaces one or morehydrogen atoms in a molecular entity.

The term “halogen group” means —F, —Cl, —Br or —I.

The term “organohalide” means an organic compound that includes at leastone halogen group.

The term “haloorganoboronic acid” means an organoboronic acid in whichthe organic group bonded to the boron through a boron-carbon bondincludes a halogen group or a pseudohalogen group.

The term “pseudohalogen group” means a group that has chemicalreactivity similar to that of a halogen group. Examples of pseudohalogengroups include triflate (—O—S(═O)₂—CF₃), methanesulfonate(—O—S(═O)₂—CH₃), cyanate

(—C≡N), azide (—N₃) thiocyanate (—N═C═S), thioether (—S—R), anhydride(—C(═O)—O—C(═O)—R), and phenyl selenide (—Se—C₆H₅).

The term “organo-pseudohalide” means an organic compound that includesat least one pseudohalogen group.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be better understood with reference to the followingdrawings and description. The components in the figures are notnecessarily to scale and are not intended to accurately representmolecules or their interactions, emphasis instead being placed uponillustrating the principles of the invention.

FIG. 1 represents chemical structures, reaction schemes and productyields for examples of the formation of a protected organoboronic acidfrom 2-bromo pyridine at various reaction temperatures.

FIG. 2 represents chemical structures, reaction schemes and productyields for examples of the formation of protected organoboronic acidsfrom various halogen-substituted heterocyclic compounds.

FIG. 3 represents chemical structures and reaction schemes for examplesof the formation of protected organoboronic acids from varioushalogen-substituted heterocyclic compounds containing two ringheteroatoms.

FIG. 4 represents chemical structures, reaction schemes and productyields for examples of the formation of protected organoboronic acidsfrom various Grignard reagents.

FIG. 5 represents chemical structures and reaction schemes for examplesof the formation of protected organoboronic acids from variousheterocyclic compounds.

FIG. 6 represents chemical structures, reaction schemes and productyields for examples of the formation of 5-bromopentanyl MIDA boronatethrough two different synthetic methods.

FIG. 7 represents chemical structures, reaction schemes and productyields for examples of the formation of protected organoboronic acidsfrom various boronic acids, using MIDA anhydride.

FIG. 8 represents a method of performing a cross-coupling reaction usinga protected organoboronic acid.

FIGS. 9A-C: A. A strategy for ICC of halogen-masked bifunctionalbuilding blocks. B. Core building blocks to enable general access tostereoisomeric iodopolyenyl MIDA boronates. C. Iodo-polyenyl MIDAboronates for the synthesis of natural products.

FIG. 10 depicts the synthesis of bifunctional MIDA boronate buildingblocks (E)-1 and (Z)-1 from the common intermediate ethynyl MIDAboronate.

FIG. 11 depicts the stereocontrolled preparation of (Z)-2.

FIG. 12 depicts the efficient and stereospecific syntheses of allpossible stereoisomers of 3 via metal-selective ICC.

FIG. 13 depicts the preparation of iodotrienyl MIDA boronate (E,E,E)-4via metal-selective ICC.

DETAILED DESCRIPTION

In accordance with the present invention a first method of forming aprotected boronic acid includes reacting in a reaction mixture animino-di-carboxylic acid, and an organoboronate salt represented byformula (I):

[R¹—B(OR²)(OR³)(OR⁴)]⁻M⁺  (I),

and forming a protected organoboronic acid represented by formula (III)in the reaction mixture:

In formulas (I) and (III), R¹ is an organic group. In formula (I) R², R³and R⁴ independently are an alkyl group or an aryl group, and M⁺ is ametal ion, a metal halide ion or an ammonium ion. In formula (III), R¹⁰,R¹¹, R¹², R¹³ and R¹⁴ independently are a hydrogen group or an organicgroup. The reaction mixture includes a polar aprotic solvent, and thereacting includes maintaining the reaction mixture at a temperature ofat least 100° C.

An example of the method of forming a protected boronic acid by reactionof an organoboronate salt with an imino-di-carboxylic acid isrepresented in the following reaction scheme:

where the compound represented by formula (II) is theimino-di-carboxylic acid.

The R¹ group, in formulas (I) and (III), is bonded to the boron througha B—C bond. The R¹ group may be an alkyl group, a heteroalkyl group, analkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynylgroup, an aryl group, a heteroaryl group, or a combination of at leasttwo of these groups. Moreover, R¹ may include one or more substituentgroups, which may include a heteroatom bonded to a carbon of the alkyl,heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl,and/or heteroaryl group.

The R¹ group may include one or more functional groups. Examples offunctional groups that may be present as part of R¹ include halogen orpseudohalogen (—X), alcohol (—OH), aldehyde (—CH═O), ketone (>C(═O)),carboxylic acid (—C(═O)OH), thiol (—SH), sulfone, sulfoxide, amine,phosphine, phosphite, phosphate, and combinations of these. Moreover,examples of functional groups that may be present as part of R¹ includemetal-containing groups, such as groups that contain metals such as tin(Sn), zinc (Zn), silicon (Si), boron, and combinations of these.

Examples of functional groups that may be present as part of R¹ includeprotected alcohols, such as alcohols protected as silyl ethers, forexample trimethylsilyl ether (TMS), t-butyldiphenylsilyl ether (TBDPS),t-butyldimethylsilyl ether (TBDMS), triisopropylsilyl ether (TIPS);alcohols protected as alkyl ethers, for example methoxymethyl ether(MOM), methoxyethoxymethyl ether (MEM), p-methoxybenzyl ether (PMB),tetrahydropyranyl ether (THP), methylthiomethyl ether; and alcoholsprotected as carbonyl groups, such as acetate or pivaloylate. Examplesof functional groups that may be present as part of R¹ include protectedcarboxylic acids, such as carboxylic acids protected as esters, forexample methyl ester, t-butyl ester, benzyl ester and silyl ester.Examples of functional groups that may be present as part of R¹ includeprotected amines, such as amines protected as carbamates, for exampleN-(trimethyl-silyl)-ethoxycarbamate (Teoc), 9-fluorenylmethyl carbamate(FMOC), benzylcarbamate (CBZ), t-butoxycarbamate (t-BOC); and aminesprotected as benzylamines.

In another example, the R¹-group may be represented by formula (IV):

Y—R⁵—(R⁶)_(m)—  (IV),

where Y represents a halogen group or a pseudohalogen group; R⁵represents an aryl group or a heteroaryl group; R⁶ represents an alkylgroup, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, analkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group,or a combination of at least two of these groups; and m is 0 or 1. R⁵may be, for example, a heteroaryl group. Moreover, R⁵ and R⁶independently may include one or more substituent groups, which mayinclude a heteroatom bonded to a carbon of the R⁵ or R⁶ group. The R⁵and R⁶ groups independently also may include one or more functionalgroups, as described for R¹ above. In one example, m is 1, and R⁶includes a 2-heterocyclic group.

For the protected organoboronic acid represented by formula (III), whenR¹ is represented by formula (IV), the protected organoboronic acid is aprotected haloorganoboronic acid or pseudohaloorganoboronic acid. TheY-group may undergo Suzuki-Miyaura cross-coupling with another compoundthat includes a free boronic acid group, without reaction of the boronof the protected organoboronic acid. Deprotection of the boron providesthe free boronic acid group, which may then undergo Suzuki-Miyauracross-coupling with another compound that includes a halogen group or apseudohalogen group. These protected haloorganoboronic acids thus may beused as bifunctional building blocks for iterative synthesis throughselective Suzuki-Miyaura transformations.

Preferably R¹ includes a heterocyclic group, an alkynyl group or analkenyl group. Examples of heterocyclic groups include groups formedfrom a heterocyclic compound such as pyridine, indole, isoindole,indazole, purine, indolizidine, quinoline, isoquinoline, quinazoline,pteridine, quinolizidine, pyrrole, pyrazine, pyridazine, pyrimidine,imidazole, pyrasole, isoxazole, oxazole, thiazole, benzthiazole, furan,benzofuran, thiophene and benzothiophene.

Preferably R¹ is a 2-heterocyclic group, in which the group is bonded tothe boron at the 2-position of the heterocyclic ring. Examples of2-heterocyclic groups include 2-pyridyl, 2-indolyl, 2-isoindolyl,2-indazolyl, 2-purinyl, 2-indolizidinyl, 2-quinolinyl, 2-isoquinolinyl,2-quinazolinyl, 2-pteridinyl, 2-quinolizidinyl, 2-pyrrolyl, 2-pyrazinyl,2-pyridazinyl, 2-pyrimidinyl, 2-imidazolyl, 2-pyrasolyl, 2-isoxazolyl,2-oxazolyl, 2-thiazolyl, 2-benzthiazolyl, 2-furyl, 2-benzofuryl,2-thiophenyl, and 2-benzthiophenyl. These groups independently also mayinclude one or more substituent groups, which may include a heteroatombonded to a carbon of the 2-heterocyclic group. Substituent groups, ifpresent, may include one or more functional groups.

Preferably R¹ includes a 2-heterocyclic group containing nitrogen at the1-position in the heterocyclic group. Examples of 2-heterocyclic groupscontaining nitrogen at the 1-position in the heterocyclic group include2-pyridyl, 2-pyrazinyl, 2-thiazolyl, 2-pyrimidinyl,2-(N-butoxycarbonyl-pyrollyl), and 2-(N-phenylsulfonate-indolyl).

The R², R³ and R⁴ groups independently are an alkyl group or an arylgroup. Preferably R², R³ and R⁴ independently are an alkyl group or anaryl group having from 1 to 10 carbon atoms, and more preferably havingfrom 1 to 6 carbon atoms. Preferably R², R³ and R⁴ independently are analkyl group having from 1 to 4 carbon atoms, and more preferably havingfrom 1 to 3 carbon atoms. Preferred groups for R², R³ and R⁴ includemethyl (—CH₃) and isopropyl (—CH(CH₃)₂) groups. Preferably two or threeof R², R³ and R⁴ are identical. Preferably R², R³ and R⁴ are identicaland are methyl or isopropyl groups.

The M⁺ ion is a counterion for the organoboronate anion. The M⁺ ion is ametal ion, a metal halide ion or an ammonium ion. Preferably M⁺ is analkali metal ion, a transition metal ion, an alkaline earth metal halideion, or a transition metal halide ion. Examples of M⁺ include Li⁺, Na⁺,K⁺, MgX⁺, CaX⁺, Zn⁺, Bu₄N⁺, where X is F, Cl, Br or I. Preferably M⁺ isLi⁺ or MgX⁺.

The organoboronate salt represented by formula (I) may be formed by anyof a variety of methods for forming boronate salts. In one example, anorganohalide or an organo-pseudohalide is reacted with an organolithiumreagent and then with a boronate ester, to form the organoboronate salthaving Li⁺ as the counterion to the organoboronate anion. This examplemay be represented by the following reaction scheme:

where R¹-R⁴ are as described above, R⁷ is a hydrocarbon group, and Y isa halogen or a pseudohalogen. The organohalide is represented by formula(V), and the organoboronate salt is represented by formula (VI).

In another example, an organic compound is reacted with a firstorganolithium reagent to form a second organolithium reagent in which a—H group from the organic compound has been replaced with a —Li group.This second organolithium reagent is then reacted with a boronate ester,to form the organoboronate salt having Li⁺ as the counterion to theorganoboronate anion. This example may be represented by the followingreaction scheme:

where R¹-R⁴ are as described above, and R⁷ is a hydrocarbon group. Theorganic compound is represented by formula (VII), the secondorganolithium reagent is represented by formula (VIII), and theorganoboronate salt is represented by formula (VI). One potentialadvantage to this method of forming the organoboronate salt is that thepool of potential organic groups (R¹) may be larger, since the source ofthe organic group does not need to include a halogen or pseudohalogengroup.

In another example, a Grignard reagent is reacted with a boronate ester,to form the organoboronate salt having MgX⁺ as the counterion to theorganoboronate anion. In a further example, the Grignard reagentoptionally may be formed by reacting an organic compound with a mixedMg/Li 2,2,6,6-tetramethylpiperidyl amide (Krasovskiy, A. Angew. Chem.Int. Ed. 2006, 45, 2958-2961). These examples may be represented by thefollowing reaction scheme:

where R¹-R⁴ are as described above. The Grignard reagent is representedby formula (IX), and the organoboronate salt is represented by formula(X). For the optional formation of the Grignard reagent, the organiccompound represented by formula (VII) may be reacted with the mixedMg/Li 2,2,6,6-tetramethylpiperidyl amide to provide the Grignard reagentrepresented by formula (IX).

The R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ groups, in formulas (II) and (III),independently are a hydrogen group or an organic group. R¹⁰, R¹¹, R¹²,R¹³ and R¹⁴ independently may be an alkyl group, a heteroalkyl group, analkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynylgroup, an aryl group, a heteroaryl group, or a combination of at leasttwo of these groups. If R¹⁰ is an organic group, the imino-di-carboxylicacid of formula (II) is an N-substituted imino-di-carboxylic acid. Inone example, R¹⁰ is methyl, and each of R¹¹, R¹², R¹³ and R¹⁴ ishydrogen. In this example, the imino-di-carboxylic acid represented byformula (II) is N-methyliminodiacetic acid (MIDA).

The protected organoboronic acid represented by formula (III) includesboron having sp³ hybridization, and the protecting group bonded to theboron is a conformationally rigid protecting group. Conformationallyrigid protecting groups for boron are described, for example, incopending U.S. patent application Ser. No. 11/937,338, entitled “SystemFor Controlling the Reactivity of Boronic Acids”, with inventors MartinD. Burke et al., published as US 2009/0030238, which is incorporatedherein by reference. Conformational rigidity of an organic protectinggroup bonded to a boron atom is determined by the following“conformational rigidity test”. A 10 mg sample of a compound including aboron atom and an organic protecting group bonded to the boron isdissolved in dry d₆-DMSO and transferred to an NMR tube. The sample isthen analyzed by ¹H-NMR at temperatures ranging from 23° C. to 150° C.At each temperature, the sample shim is optimized, and a ¹H-NMR spectrumobtained. If the protecting group is not conformationally rigid, thensplit peaks for a set of diastereotopic protons in the ¹H-NMR spectrumobtained at 23° C. will coalesce into a single peak in the ¹H-NMRspectrum obtained at 100° C. If the protecting group is conformationallyrigid, then split peaks for a set of diastereotopic protons in the¹H-NMR spectrum obtained at 23° C. will remain split, and will notcoalesce into a single peak in the ¹H-NMR spectrum obtained at 90° C.

In one example the organoboronate salt represented by formula (I) isreacted with MIDA, producing a protected organoboronic acid representedby formula (III) in which R²⁰ is methyl, and each of R²¹, R²², R²³ andR²⁴ is hydrogen. The protected organoboronic acid of this example may berepresented by formula (XI):

The reaction mixture includes a polar aprotic solvent. Examples of polaraprotic solvents include tetrahydrofuran (THF), dioxane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene and xylene.Preferably the reaction mixture includes DMSO.

The reacting includes maintaining the reaction mixture at a temperatureof at least 100° C. Preferably the reacting includes maintaining thereaction mixture at a temperature of at least 110° C., more preferablyof at least 115° C. Preferably the reacting includes maintaining thereaction mixture at a temperature of from 100° C. to 200° C., morepreferably from 100° C. to 175° C., more preferably from 110° C. to 150°C., and more preferably from 115° C. to 125° C.

Previously, it was believed that protected 2-heterocyclic organoboronicacids that included a MIDA boronate protecting group were susceptible todegradation when maintained in solution over 100° C. Surprisingly, ithas now been discovered that 2-heterocyclic MIDA boronates can be stableat temperatures of a least 100° C., including temperatures of at least110° C. and at least 115° C., and including temperatures of from 100° C.to 200° C., from 100° C. to 175° C., from 110° C. to 150° C., and from115° C. to 125° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen.

In certain embodiments of the aforementioned methods, the polar aproticsolvent is selected from the group consisting of tetrahydrofuran (THF),dioxane, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), tolueneand xylene.

In certain embodiments of the aforementioned methods, the reactionmixture is at a temperature of from 100° C. to 200° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the polar aprotic solventis selected from the group consisting of tetrahydrofuran (THF), dioxane,dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), toluene and xylene.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the reaction mixture isat a temperature of from 100° C. to 200° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; the polar aprotic solvent isselected from the group consisting of tetrahydrofuran (THF), dioxane,dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), toluene and xylene;and the reaction mixture is at a temperature of from 100° C. to 200° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; the polar aprotic solvent isselected from the group consisting of tetrahydrofuran (THF), dioxane,dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), toluene and xylene;and the reaction mixture is at a temperature of from 100° C. to 175° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the polar aprotic solventis dimethyl sulfoxide (DMSO).

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the polar aprotic solventis dimethyl sulfoxide (DMSO), toluene and xylene; and the reactionmixture is at a temperature of from 100° C. to 200° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the polar aprotic solventis dimethyl sulfoxide (DMSO); and the reaction mixture is at atemperature of from 100° C. to 175° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the polar aprotic solventis dimethyl sulfoxide (DMSO); and the reaction mixture is at atemperature of from 100° C. to 150° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the polar aprotic solventis dimethyl sulfoxide (DMSO); and the reaction mixture is at atemperature of from 100° C. to 125° C.

FIG. 1 represents chemical structures, reaction schemes and productyields for examples of the formation of 2-pyridyl MIDA boronate 2a from2-bromo pyridine 1a at various reaction temperatures. The lithium2-pyridyl (triisopropyl)borate salt 3 can be formed by reaction of the2-bromo pyridine 1a with n-butyl lithium (nBuLi) and triisopropylboronate ester at −78° C. Although 3 is an effective reagent in othercontexts, only a low yield of 4% of 2a was obtained when afreshly-prepared solution of 3 in THF was added to a stirred suspensionof MIDA in DMSO at 50° C. The major byproducts observed in this reactionwere pyridine and boric acid, which were consistent with competitionbetween the formation of 2a and the protodeborylation of the notoriouslylabile 2-pyridyl—boron bond in 3. Attempts to avoid the undesirableprotodeborylation by utilizing lower reaction temperatures did notimprove the yield of 2a.

Surprisingly, increasing the reaction temperature from 50° C. to 110° C.provided a 10-fold increase in the yield of 2a. Also surprisingly, afurther increase in the reaction temperature to 150° C. provided anincrease in the yield to 58%. The unexpected stability of 2a attemperatures of at least 100° C. was confirmed by maintaining theprotected organoboronic acid in solution in DMSO at 130° C. for onehour, while monitoring the solution by ¹H NMR. One possible explanationfor these surprising and unexpected results is that the undesiredprotodeborylation occurs prior to MIDA complexation. Thus, a higherreaction temperature enables a more rapid ligand exchange, which favorsthe formation of stable MIDA boronate 2a prior to the decomposition ofits precursor 3.

FIG. 2 represents chemical structures, reaction schemes and productyields for xamples of the formation of protected organoboronic acids2a-2h from the various halogen-substituted heterocyclic compounds 1a-1h.The reaction of 2-bromo pyridine 1a with nBuLi and triisopropyl boronateester at −78° C., followed by reaction of the resulting lithium2-pyridyl (triisopropyl)borate salt with MIDA, was reproduced on amultigram scale to provide 2-pyridyl MIDA boronate 2a in 64% isolatedyield (FIG. 2, entry 1). This protected organoboronic acid has beenstored as a solid under an air atmosphere for more than 1 year withoutmeasurable decomposition.

Referring still to FIG. 2, a variety of halogen-substituted heterocycliccompounds 1b-1i may be reacted with nBuLi and triisopropyl boronateester at −78° C., followed by a reaction of the resulting lithium2-heterocyclic (triisopropyl)borate salts with MIDA, to form thecorresponding 2-heterocyclic MIDA boronates 2b-21. The 6-, 5-, and4-methyl-2-pyridyl subunits appear in a wide variety of interesting anduseful molecules, including pharmaceuticals, materials, and metalligands, and the corresponding MIDA boronate building blocks 2b-d can beaccessed readily using this method (FIG. 2, entries 2-4). The6-methoxy-, and 6-, 5-, and 4-trifluoromethyl-2-pyridyl subunitsrepresent a range of hydrogen bond donors and acceptors, as well aselectron-withdrawing and electron-releasing groups, and thecorresponding MIDA boronates 2e-2h were all prepared with this sameprocedure (FIG. 2, entries 5-8). Bromo-substituted 2-pyridyl MIDAboronate 2i and has the potential for a range of iterativecross-coupling applications, due to the presence of an aryl halidefunctionality in the protected organoboronic acid. Remarkably, each ofthe synthetic building blocks 2a-i is air- and chromatographicallystable, highly crystalline, monomeric, and a free-flowing solid. Manyaryl and heteroaryl bromides, including 2-bromopyridine, arecommercially available and inexpensive. Thus, the method of forming aprotected boronic acid by reaction of an organoboronate salt with animino-di-carboxylic acid can provide straightforward access to acollection of air-stable 2-pyridyl building blocks, which isadvantageous to research in drug discovery.

FIG. 3 represents chemical structures and reaction schemes for examplesof the formation of protected organoboronic acids 5a-5e from varioushalogen-substituted heterocyclic compounds containing two ringheteroatoms 4a-4e. The 2-pyrazine and thiazole subunits are important inmedicinal chemistry, and the method of forming a protected boronic acidby reaction of an organoboronate salt with an imino-di-carboxylic acidsuccessfully provided access to the 2-pyrazine MIDA boronates 5a-b (FIG.4, entries 1 and 2) and to the thiazole MIDA boronates 5c-5e (FIG. 4,entries 3-5). The yield of 2-pyrazine MIDA boronate 5a was 43%. Theyield of 5-thiazolyl MIDA boronate 5e was 44%.

FIG. 4 represents chemical structures, reaction schemes and productyields for examples of the formation of protected organoboronic acids7a-7c from various Grignard reagents 6a-6c. The yields of protectedorganoboronic acids 7a-7c were 50%, 77% and 43%, respectively. Thus, anorganoboronate salt having a MgBr⁺ counterion instead of a Li⁺counterion can be reacted with MIDA in a polar aprotic solvent at atemperature of at least 100° C. to provide the corresponding protectedorganoboronic acid.

FIG. 5 represents chemical structures and reaction schemes for examplesof the formation of protected organoboronic acids 9a-9h from variousheterocyclic compounds 8a-8h. The heterocyclic compounds 8a-8h areexpected to react with MIDA in a polar aprotic solvent at a temperatureof at least 100° C. to provide the corresponding protected organoboronicacids 9a-9h once the heterocyclic compounds have been transformed intothe corresponding organoboronate salts.

The reagents used in the method of forming a protected boronic acid byreaction of an organoboronate salt with an imino-di-carboxylic acid canbe obtained readily and at relatively low cost. The MIDA ligand can beprepared on the kilogram scale from the commodity chemicalsiminodiacetic acid, formic acid, and formaldehyde, of which formic acidis the most expensive reagent. Moreover, MIDA is non-toxic, indefinitelyair-stable, and biodegradable. The highly-crystalline and air-stablenature of MIDA boronates greatly facilitates their isolation,purification, and storage. Thus, the method of forming a protectedboronic acid by reaction of an organoboronate salt with animino-di-carboxylic acid may provide scalable and economical access to awide range of 2-heterocyclic and other types of complex and/or importantMIDA boronate building blocks.

In accordance with the present invention a second method of forming aprotected boronic acid includes reacting in a reaction mixture aN-substituted morpholine dione, and an organoboronic acid represented byformula (XII):

R¹—B(OH)₂  (XII),

and forming a protected organoboronic acid represented by formula (III)in the reaction mixture:

In formulas (III) and (XII), R¹ is an organic group as described abovefor formulas (I) and (III). In formula (III), R¹⁰ is an organic group,and R¹¹, R¹², R¹³ and R¹⁴ independently are a hydrogen group or anorganic group as described above for formula (III). The reaction mixturemay include a polar aprotic solvent, and the reacting may includesmaintaining the reaction mixture at a temperature of at most 100° C.

An example of the method of forming a protected boronic acid isrepresented in the following reaction scheme:

where the compound represented by formula (XIII) is the N-substitutedmorpholine dione.

In one example, the organoboronic acid represented by formula (XII) isreacted with N-methyl morpholine dione, producing a protectedorganoboronic acid represented by formula (III) in which R¹⁰ is methyl,and each of R¹¹, R¹², R¹³ and R²⁴ is hydrogen. An example of this methodis represented in the following reaction scheme:

where the protected organoboronic acid is represented by formula (XI),and the N-methyl morpholine dione is represented by formula (XIV). Thereagent N-methyl morpholine dione also is referred to herein as “MIDAanhydride”, due to its similarity to the MIDA reagent and MIDAprotecting group.

The reaction mixture includes a polar aprotic solvent. Examples of polaraprotic solvents include tetrahydrofuran (THF), dioxane, acetonitrile,dimethyl formamide (DMF), toluene and xylene. Preferably the reactionmixture includes THF.

The reacting includes maintaining the reaction mixture at a temperatureof at most 100° C. Preferably the reacting includes maintaining thereaction mixture at a temperature of at most 90° C., preferably of atmost 80° C. or at most 70° C. Preferably the reacting includesmaintaining the reaction mixture at a temperature of from 40° C. to 100°C., more preferably from 50° C. to 90° C., and more preferably from 60°C. to 80° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen.

In certain embodiments of the aforementioned methods, the polar aproticsolvent is selected from the group consisting of tetrahydrofuran (THF),dioxane, acetonitrile, dimethyl formamide (DMF), toluene and xylene.

In certain embodiments of the aforementioned methods, the reactionmixture is maintained at a temperature of from 40° C. to 100° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the polar aprotic solventis selected from the group consisting of tetrahydrofuran (THF), dioxane,acetonitrile, dimethyl formamide (DMF), toluene and xylene.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the polar aprotic solventis the polar aprotic solvent is THF.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; and the reaction mixture ismaintained at a temperature of from 40° C. to 100° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; the polar aprotic solvent isselected from the group consisting of tetrahydrofuran (THF), dioxane,acetonitrile, dimethyl formamide (DMF), toluene and xylene; and thereaction mixture is maintained at a temperature of from 40° C. to 100°C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; the polar aprotic solvent isselected from the group consisting of tetrahydrofuran (THF), dioxane,acetonitrile, dimethyl formamide (DMF), toluene and xylene; and thereaction mixture is maintained at a temperature of from 50° C. to 90° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; the polar aprotic solvent isselected from the group consisting of tetrahydrofuran (THF), dioxane,acetonitrile, dimethyl formamide (DMF), toluene and xylene; and thereaction mixture is maintained at a temperature of from 60° C. to 80° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; the polar aprotic solvent istetrahydrofuran (THF); and the reaction mixture is maintained at atemperature of from 40° C. to 100° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; the polar aprotic solvent istetrahydrofuran (THF); and the reaction mixture is maintained at atemperature of from 50° C. to 90° C.

In certain embodiments of the aforementioned methods, R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen; the polar aprotic solvent istetrahydrofuran (THF); and the reaction mixture is maintained at atemperature of from 60° C. to 80° C.

FIG. 6 represents chemical structures, reaction schemes and productyields for examples of the formation of 5-bromopentanyl MIDA boronate11a through two different synthetic methods. Simply heating a solutionof 10a and MIDA anhydride (formula XIV) in THF for 14-24 hours producedan 88% yield of 11a (FIG. 6, entry 2). In contrast, reaction of 10a withMIDA using the conventional Dean-Stark conditions (PhMe:DMSO 10:1),resulted in substantial decomposition of the boronic acid, resulting ina low yield of 11a (FIG. 6, entry 1).

FIG. 7 represents chemical structures, reaction schemes and productyields for examples of the formation of protected organoboronic acids11a-11f from various boronic acids 10b-10f, using MIDA anhydride. Thereaction of chloromethyl boronic acid 10b with MIDA under theconventional Dean-Stark conditions provided little to none of thedesired product. In contrast, reacting 10b with MIDA anhydride providedthe novel chloromethyl MIDA boronate 11b in good yield (FIG. 7, entry1). The method of forming a protected boronic acid by reaction of anorganoboronic acid with a N-substituted morpholine dione also waseffective with aryl, heteroaryl, and cycloalkyl derivatives (FIG. 7,entries 2-5). It is expected that this method will be effective with awide range of alkenyl boronic acids, and that it will be effective forboronic acids that are acid sensitive, such as Boc-protected pyrrolesand indoles.

The reagents used in the method of forming a protected boronic acid byreaction of an organoboronic acid with a N-substituted morpholine dionecan be obtained readily and at relatively low cost. The MIDA anhydridereagent is a colorless, air-stable, highly crystalline solid that can beprepared easily and can be purified by simple recrystallization on ascale of 100 g or more. MIDA anhydride is neutral and is more solublethan the MIDA reagent, and MIDA anhydride can be used to provide aprotected organoboronic acid simply by refluxing the MIDA anhydride withthe corresponding unprotected organoboronic acid, without the need forDean-Stark dehydration.

Relative to the conventional Dean-Stark conditions using MIDA as areagent, the method of forming a protected boronic acid by reaction ofan organoboronic acid with a N-substituted morpholine dione can providea convenient, mild, non-acidic and DMSO-free procedure for preparing awide range of MIDA boronates. This remarkably simple method may provideefficient and economical access to a wide range of MIDA boronates fromthe corresponding readily-available boronic acids. Thus, the method hasthe potential to expand substantially the pool of MIDA boronates forpotential applications in iterative cross-coupling, new building blocksyntheses, and slow release cross-coupling.

The protected organoboronic acids provided by either of the abovemethods are readily purified by column chromatography. This is a uniquecharacteristic of MIDA boronate esters, as conventional organoboronicacids typically are unstable to chromatographic techniques. Theseprotected organoboronic acids also may be crystalline, which canfacilitate purification, utilization, and storage. These protectedorganoboronic acids are stable to long term storage, including storageon the bench top under air. This is also a unique characteristic of MIDAboronate esters, as many organoboronic acids are unstable to long termstorage.

FIG. 8 represents a method 800 of performing a chemical reaction,including reacting 810 a protected organoboronic acid 820 and anorganohalide or organo-pseudohalide 830, to provide a cross-coupledproduct 840. R^(A) and R^(C) independently are organic groups, and Y isa halogen group or a pseudohalogen group. The reacting 810 may includecontacting the protected organoboronic acid 820 and the organohalide ororgano-pseudohalide 830 with a palladium catalyst in the presence of abase. The base may be a mild base, such as a base having a pK_(B) of atleast 1. The protecting group may be removed from the boron atom insitu, providing a corresponding unprotected organoboronic acid, whichcan then cross-couple with the organohalide or organo-pseudohalide 830.The protected organoboronic acid 820 includes a boron having an sp³hybridization and a conformationally rigid protecting group, and theorganic group R^(A) is bonded to the boron through a B—C bond.Preferably the protected organoboronic acid 820 includes a trivalentprotecting group bonded to the boron.

The compound 830 with which the protected organoboronic acid 820 isreacted may be an organohalide or an organo-pseudohalide. The compound830 may be an organohalide, which is an organic compound that includesat least one halogen group. Examples of halogen groups that may bepresent in an organohalide compound include —F, —Cl, —Br or —I. Thecompound 830 may be an organo-pseudohalide, which is an organic compoundthat includes at least one pseudohalogen group. Examples ofpseudohalogen groups that may be present in an organo-pseudohalidecompound include triflate (—O—S(═O)₂—CF₃), methanesulfonate(—O—S(═O)₂—CH₃), cyanate (—C≡N), azide (—N₃) thiocyanate (—N═C═S),thioether (—S—R), anhydride (—C(═O)—O—C(═O)—R), and phenyl selenide(—Se—C₆H₅). The halogen or pseudo-halogen group may be bonded to analkyl group, a heteroalkyl group, an alkenyl group, a heteroalkenylgroup, an alkynyl group, a heteroalkynyl group, an aryl group, aheteroaryl group, or a combination of at least two of these groups.

The compound 830 with which the protected organoboronic acid is reactedmay be an organohalide or an organo-pseudohalide in which the halogen orpseudo-halogen group is bonded to an aryl group or a heteroaryl group.In one example, the compound is an unactivated aryl chloride or anunactivated heteroaryl chloride. Unactivated aryl chlorides, which donot contain any electron-withdrawing groups, typically react more slowlythan aryl bromides or activated aryl chlorides in cross-couplingreactions.

The reaction mixture includes a base, and preferably the base has apK_(B) of at least 1. Preferably the base has a pK_(B) of at least 1.5,more preferably of at least 2, more preferably of at least 3. Examplesof bases having a pK_(B) of at least 1 include bases that include ananion selected from [PO₄]³⁻, [C₆H₅O]⁻, [CO₃]²⁻ and [HCO₃]¹⁻, such asalkali and alkaline earth salts of these anions. Specific examples ofsuch bases include Li₃PO₄, Na₃PO₄, K₃PO₄, Li⁺ [C₆H₅O]⁻, Na⁺ [C₆H₅O]⁻,K⁺[C₆H₅O]⁻, Li₂CO₃, Na₂CO₃, K₂CO₃, MgCO₃, CaCO₃, LiHCO₃, NaHCO₃, andKHCO₃.

Preferably the reaction mixture includes a solvent. Examples of solventsinclude protic solvents such as water, methanol, ethanol, isopropylalcohol (IPA) and butanol. Examples of solvents include aprotic solventssuch as tetrahydrofuran (THF), dioxane, dimethyl formamide (DMF),toluene and xylene. The reaction mixture may include a mixture of two ormore solvents, which independently may be a protic or aprotic solvent.Preferably the reaction mixture includes a protic solvent. A proticsolvent may facilitate dissociation of the base in the reaction mixture.

The reaction mixture may include other ingredients, such as acopper-containing compound and/or a fluoride anion source. Examples ofcopper-containing compounds include CuI, CuCl and Cu(OAc)₂. Examples offluoride anion sources include KF, NaF, and CsF.

Forming a cross-coupled product in the reaction mixture may includemaintaining the reaction mixture at a temperature and for a timesufficient to form a cross-coupled product 840. For example, forming across-coupled product in the reaction mixture may include maintainingthe reaction mixture at a temperature from 0° C. to 200° C. Preferablythe forming includes maintaining the reaction mixture at a temperaturefrom 25° C. to 150° C., and more preferably includes maintaining thereaction mixture at a temperature from 50° C. to 120° C. Forming across-coupled product in the reaction mixture may include maintainingthe reaction mixture for a period of 1 hour to 100 hours. Preferably theforming includes maintaining the reaction mixture for a period of 2hours to 72 hours, and more preferably includes maintaining the reactionmixture for a period of 4 hours to 48 hours. Preferably the forming across-coupled product in the reaction mixture includes maintaining thereaction mixture at a temperature from 25° C. to 150° C. for a period of2 hours to 72 hours, and more preferably includes maintaining thereaction mixture at a temperature from 50° C. to 120° C. for a period of4 hours to 48 hours.

The yield of cross-coupled product 840 in the reaction mixture may be atleast 50%. Preferably the yield of cross-coupled product in the reactionmixture from this method is at least 60%. More preferably the yield ofcross-coupled product in the reaction mixture from this method is atleast 70%, more preferably is at least 75%, more preferably is at least80%, more preferably is at least 85%, more preferably is at least 90%,more preferably is at least 95%, and more preferably is at least 99%.

The following examples are provided to illustrate one or more preferredembodiments of the invention. Numerous variations can be made to thefollowing examples that lie within the scope of the invention.

EXAMPLES General Methods

Commercial reagents were purchased from Sigma-Aldrich (St. Louis, Mo.),Fisher Scientific (Waltham, Mass.), Alfa Aesar/Lancaster Synthesis (WardHill, Mass.), TCI America (Portland, Oreg.), Frontier Scientific (Logan,Utah), Oakwood Products (West Columbia, S.C.) or Combi-Blocks (SanDiego, Calif.) and were used without further purification unlessotherwise noted. Solvents were purified via passage through packedcolumns as described by Pangborn and coworkers (Pangborn, A. B, et al.Organometallics 1996, 15, 1518-1520) (THF, Et₂O, CH₃CN, CH₂Cl₂: dryneutral alumina; hexane, benzene, and toluene, dry neutral alumina andQ5 reactant (copper(II) oxide on alumina); DMSO, DMF: activatedmolecular sieves). All water was deionized prior to use. Triethylamine,diisopropylamine, diethylamine, pyridine, and 2,6-lutidine were freshlydistilled under an atmosphere of nitrogen from CaH₂.N-methyliminodiacetic acid was prepared according to procedures reportedin the literature (Ballmer, S. G.; Gillis, E. P.; Burke, M. D. Org. Syn.2009, 86, 344-359).

Unless otherwise noted, all reactions were performed in flame-driedglassware under argon. Organic solutions were concentrated via rotaryevaporation under reduced pressure with a bath temperature of 20-60° C.Reactions were monitored by analytical thin layer chromatography (TLC)performed using the indicated solvent on E. Merck silica gel 60 F254plates (0.25 mm). Compounds were visualized by exposure to a UV lamp(λ=254 or 366 nm) and/or treatment with a solution of KMnO₄, followed bybrief heating with a Varitemp® heat gun (Master Appliance; Racine,Wis.).

Column chromatography was performed using standard methods (Still, 1978)or with a CombiFlash R_(f) (Teledyne-Isco; Lincoln, Nebr.) purificationsystem. Both methods were performed using Merck silica gel grade 9385 60Å (230-400 mesh). For loading, compounds were adsorbed onto nonacid-washed Celite 545 (approximately 10 g/mmol crude product) in vacuofrom an acetone solution. Specifically, in each case the crude residuewas dissolved/suspended in acetone and to the mixture was added Celite.The mixture was concentrated in vacuo to afford a free flowing powderwhich was then loaded on top of a silica gel column. To ensurequantitative transfer, this procedure was repeated with a small amountof acetone and Celite to transfer any remaining residue. MIDA boronateswere compatible with standard silica gel chromatography, includingstandard loading techniques.

¹H-NMR spectra were recorded at 23° C. on a Varian Unity or a VarianUnity Inova 500 MHz spectrometer (Varian; Palo Alto, Calif.). Chemicalshifts (δ) were reported in parts per million (ppm) downfield fromtetramethylsilane and referenced to residual protium in the NMR solvent(CHCl₃, δ=7.26; CD₂HCN, δ=1.93, center line; acetone-d₆ δ=2.04, centerline). Alternatively, NMR-solvents designated as “w/TMS” were referencedto tetramethylsilane (δ=0.00 ppm) added as an internal standard. Datawere reported as follows: chemical shift, multiplicity (s=singlet,d=doublet, t=triplet, q=quartet, quint=quintet, sept=septet,m=multiplet, br=broad, app=apparent), coupling constant (J) in Hertz(Hz), and integration.

¹³C NMR spectra were recorded at 23° C. on a Varian Unity 500 MHzspectrometer. Chemical shifts (δ) were reported in ppm downfield fromtetramethylsilane and referenced to carbon resonances in the NMR solvent(CDCl₃, δ=77.0, center line; CD₃CN, δ=1.30, center line, acetone-d₆δ=29.80, center line) or to added tetramethylsilane (δ=0.00). Carbonsbearing boron substituents were not observed (quadrupolar relaxation).

¹¹B NMR spectra were recorded using a General Electric Unity Inova 400MHz instrument and referenced to an external standard of (BF₃·Et₂O).High resolution mass spectra (HRMS) were performed by Furong Sun and Dr.Steve Mullen at the University of Illinois School of Chemical SciencesMass Spectrometry Laboratory. Infrared spectra were collected from athin film on NaCl plates or as KBr pellets on a Spectrum BX FT-IRspectrometer (Perkin-Elmer; Waltham, Mass.), a Mattson Galaxy SeriesFT-IR 5000 spectrometer or a Mattson Infinity Gold FT-IR spectrometer.Absorption maxima (v_(max)) were reported in wavenumbers (cm⁻¹).

Example 1 Preparation of Protected Organoboronic Acids fromCorresponding Bromides

The general method for synthesizing protected organoboronic acids was asfollows. A flame-dried, back-filled with argon 50 mL Schlenk Flask withseptum and PTFE coated magnetic stirbar was charged with halide (1 eq),triisopropyl borate (1 eq), and THF (0.5 M). The flask was cooled withstirring to −78° C. nBuLi (1 eq) was added slowly down the side of theglass at a rate of 3 mmol every five minutes. After complete addition ofthe nBuLi, the reaction was stirred for one hour at −78° C. and threehours at 23° C. A second reaction apparatus was assembled while thefirst reaction was stirring. The apparatus, consisting of a 100 mLthree-necked round bottom flask, 50 mL addition funnel, short pathdistillation apparatus, ground-glass jointed thermometer, 50 mL roundbottom flask, PTFE coated magnetic stirbar, and two septa, was flamedried under vacuum and backfilled with argon. To the three necked roundbottom flask was added MIDA (1.7 eq) and DMSO (0.85 M). The septum onthe three-necked round bottom flask was subsequently replaced with athermometer with PTFE adapter. The triisopropoxy borate salt solutionprepared in the Schlenk flask was then transferred to the additionfunnel using THF to affect a quantitative transfer. The septum on theaddition funnel was then replaced with a ground glass stopper. A 145° C.oil bath was raised to the three necked round-bottom flask and waterhoses were equipped to the short path distillation apparatus and thewater was started. After the internal temperature of the apparatusreached 115° C., the addition of the triisopropoxy borate salt solutionwas started. The addition was monitored to ensure that the internaltemperature was 110° C.-120° C. through modulation of the rate ofaddition. Approximate addition time was 45-60 minutes.

Following complete addition, the addition funnel was removed andreplaced with a ground glass stopper, and the head temperature wasallowed to drop to 50° C. The 145° C. oil bath was then dropped. Theinternal thermometer was removed and replaced with a ground glassstopper. The recovery flask was emptied and replaced. A second trapconsisting of a cold-finger and a double-necked round bottom flask wasequipped in series between the reaction apparatus and the vacuummanifold. A 50° C. oil bath was raised to the three-necked round bottomflask and a 250 mTorr vacuum was pulled on the chamber. DMSO wasdistilled until evidence of distillation ceased. The apparatus was thenbackfilled and the three necked round bottom was removed from theapparatus. The reaction was suspended using small amounts ofacetonitrile. Celite was added and the resulting mixture wasconcentrated in vacuo to afford a free flowing powder. The mixture wasplaced under a high vacuum for twelve hours to remove residual DMSO. Thereaction was loaded into a solid loading cartridge and an 80 g SiO₂chromatographic column was run. An example of this method is depicted inthe scheme below.

To form protected organoboronic acid 2-pyridyl MIDA boronate 2a, thegeneral procedure was followed using 2-bromo pyridine (840 μL, 8.6mmol), triisopropyl borate (2 mL, 8.6 mmol), THF (26 mL), DMSO (17 mL),nBuLi (3.44 mL, 2.5 M in hexanes), and N-methyliminodiacetic acid (2.15g, 14.62 mmol). The mixture was eluted using 300 mL (95% Et₂O: 5% MeCN)followed by 100% MeCN until elution of product. The appropriatefractions were concentrated, azeotroped with DCM three times and placedunder high vacuum for 20 minutes to afford 2-pyridyl MIDA boronate as anoff-white crystalline solid (1.212 g, 59%). TLC (MeCN) R_(f)=0.26,visualized by UV (6=254 nm) and KMnO₄ stain. ¹H-NMR (500 MHz, CD₃CN) δ8.67 (ddd, J=2.5, 1.5, 1.0 Hz, 1H), 7.70 (td, J=7.5, 1.5 Hz, 1H), 7.62(dt, J=7.5, 1.0 Hz, 1H), 7.28 (ddd, J=8.5, 1.5 Hz, 1H), 8.67 (ddd,J=4.5, 1.5, 1.0 Hz, 1H), 4.09 (d, J=17 Hz, 2H), 3.98 (d, J=17 Hz, 2H),2.55 (s, 3H). ¹³C-NMR (125 MHz, CD₃CN) δ 169.6, 150.8, 135.8, 128.1,124.3, 62.9, 47.6. ¹¹B-NMR (96 MHz, CD₃CN) δ 10.3. HRMS (CI+) Calculatedfor C₁₀H₁₂O₄N₂B (M+H)⁺: 235.0890; Found: 235.0895. IR (KBr, cm⁻¹) 3004,2956, 1774, 1749, 1633, 1590, 1466, 1340, 1289, 1279, 1214, 1152, 1095,1054, 1045, 998, 964, 894, 866, 775, 754, 708, 683.

To form protected organoboronic acid 6-methyl-2-pyridyl MIDA boronate2b, the general procedure was followed using 2-bromo-6-methylpyridine(980 μL, 8.6 mmol), triisopropyl borate (2 mL, 8.6 mmol), nBuLi (3.44mL, 2.5 M in hexanes), THF (26 mL), DMSO (17 mL), andN-methyliminodiacetic acid (2.15 g, 14.62 mmol). The mixture was elutedusing an ethyl acetate and acetonitrile gradient (100% EtOAc→45% EtOAc:55% MeCN). The appropriate fractions were concentrated, azeotroped withDCM three times and placed under high vacuum for 20 minutes to afford2-pyridyl 6-methyl MIDA boronate as an off-white crystalline solid(1.243 g, 58%). ¹H-NMR (500 MHz, CD₃CN) δ 7.57 (t, J=7.5 Hz, 1H), 7.40(d, J=7.5, 1H), 7.14 (d, J=7.5 Hz, 1H), 4.07 (d, J=17 Hz, 2H), 4.00 (d,J=17 Hz, 2H), 2.55 (s, 3H), 2.48 (s, 3H).

To form protected organoboronic acid 5-methyl-2-pyridyl MIDA boronate2c, the general procedure was followed using 2-bromo-5-methylpyridine(1.48 g, 8.6 mmol), triisopropyl borate (2 mL, 8.6 mmol), THF (26 mL),DMSO (17 mL), nBuLi (3.44 mL, 2.5 M in hexanes), andN-methyliminodiacetic acid (2.15 g, 14.62 mmol). The mixture was elutedusing 300 mL (95% Et₂O: 5% MeCN) followed by 100% MeCN until elution ofproduct. The appropriate fractions were concentrated, azeotroped withDCM three times and placed under high vacuum for 20 minutes to afford5-methyl-2-pyridyl MIDA boronate as an off-white crystalline solid (1.09g, 51%). ¹H-NMR (500 MHz, CD₃CN) δ 8.53 (s, 1H), 7.53 (t, J=7.5, 2H),4.07 (d, J=17 Hz, 2H), 3.96 (d, J=17 Hz, 2H), 2.53 (s, 3H), 2.31 (s,3H).

To form protected organoboronic acid 4-methyl-2-pyridyl MIDA boronate2d, the general procedure was followed using 2-bromo-4-methylpyridine(960 μL, 8.6 mmol), triisopropyl borate (2 mL, 8.6 mmol), THF (26 mL),DMSO (17 mL), nBuLi (3.44 mL, 2.5 M in hexanes), andN-methyliminodiacetic acid (2.15 g, 14.62 mmol). The mixture was elutedusing 300 ml, (95% Et₂O: 5% MeCN) followed by 100% MeCN until elution ofproduct. The appropriate fractions were concentrated, azeotroped withDCM three times and placed under high vacuum for 20 minutes to afford4-methyl-2-pyridyl MIDA boronate as an off-white crystalline solid (897mg, 42%). ¹H-NMR (500 MHz, CD₃CN) δ 8.51 (d, J=5 Hz, 1H), 7.47 (s, 1H),7.11 (d, J=5 Hz, 1H), 4.08 (d, J=17 Hz, 2H), 3.97 (d, J=17 Hz, 2H), 2.54(s, 3H), 2.33 (s, 3H).

To form protected organoboronic acid 6-methoxy-2-pyridyl MIDA boronate2e, the general procedure was followed using 2-bromo-6-methoxypyridine(1.05 mL, 8.6 mmol), triisopropyl borate (2 mL, 8.6 mmol), THF (45 mL),DMSO (17 mL), nBuLi (3.44 mL, 2.5 M in hexanes), andN-methyliminodiacetic acid (2.15 g, 14.62 mmol). The mixture was elutedusing an ethyl acetate and acetonitrile gradient. The concentratedproduct was suspended in 20 mL of MeCN and heated to 80° C. The solutionwas cooled to room temperature with stirring. The product wasprecipitated with a slow dropwise addition of 200 mL of Et₂O. Thecrystals were collected to afford 6-methoxy-2-pyridyl MIDA boronate asan off-white crystalline solid (1.83 g, 81%). ¹H-NMR (500 MHz, CD₃CN) δ7.60 (dd, J=7 Hz, 8 Hz, 1H), 7.22 (d, J=7 Hz, 1H), 6.70 (d, J=8 Hz, 1H),4.09 (d, J=16.5 Hz, 2H), 3.99 (d, J=16.5 Hz, 2H), 3.83 (s, 3H), 2.60 (s,3H).

To form protected organoboronic acid 6-trifluoromethyl-2-pyridyl MIDAboronate 2f, the general procedure was followed using2-bromo-6-trifluoromethylpyridine (1.95 g, 8.6 mmol), triisopropylborate (2 mL, 8.6 mmol), THF (26 mL), DMSO (17 mL), nBuLi (3.44 mL, 2.5M in hexanes), and N-methyliminodiacetic acid (2.15 g, 14.62 mmol). Themixture was eluted using a hexanes and ethyl acetate gradient. Theappropriate fractions were concentrated, azeotroped with DCM three timesand placed under high vacuum for 20 minutes to afford6-trifluoromethyl-2-pyridyl MIDA boronate as a tan crystalline solid(2.33 g, 90%). ¹H-NMR (400 MHz, CD₃CN) δ 7.95 (t, J=7.6 Hz, 1H), 7.87(d, J=7.2 Hz, 1H), 7.72 (dd, J=7.6 Hz, 0.8 Hz, 1H), 4.13 (d, J=16.8 Hz,2H), 3.98 (d, J=16.8 Hz, 2H), 2.57 (s, 3H).

To form protected organoboronic acid 5-trifluoromethyl-2-pyridyl MIDAboronate 2 g, the general procedure was followed using2-bromo-5-trifluoromethylpyridine (1.94 g, 8.6 mmol), triisopropylborate (2 mL, 8.6 mmol), THF (45 mL), DMSO (17 mL), nBuLi (3.44 mL, 2.5M in hexanes), and N-methyliminodiacetic acid (2.15 g, 14.62 mmol). Themixture was eluted using an ethyl acetate and acetonitrile gradient. Theconcentrated product was suspended in 8 mL of MeCN and heated to 80° C.The solution was cooled to room temperature with stirring. The productwas precipitated with a slow dropwise addition of 80 mL of Et₂O. Thecrystals were collected to afford 5-trifluoromethyl-2-pyridyl MIDAboronate as an off-white crystalline solid (1.45 g, 56%). ¹H-NMR (500MHz, CD₃CN) δ 8.99 (s, 1H), 8.00 (dd, J=8 Hz, 1.5 Hz, 1H), 7.82 (d, J=8Hz, 1H), 4.13 (d, J=17 Hz, 2H), 4.00 (d, J=17 Hz, 2H), 2.56 (s, 3H).

To form protected organoboronic acid 4-trifluoromethyl-2-pyridyl MIDAboronate 2 h, the general procedure was followed using2-bromo-4-trifluoromethyl-pyridine (1.06 mL, 8.6 mmol), triisopropylborate (2 mL, 8.6 mmol), THF (17 mL), DMSO (60 mL), nBuLi (3.44 mL, 2.5M in hexanes), and N-methyliminodiacetic acid (2.15 g, 14.62 mmol). Onemodification was made to the procedure. Instead of using THF to affect aquantitative transfer of the triisopropoxyborane salt, 43 mL of DMSO wasused. The mixture was eluted using 300 mL (95% Et₂O: 5% MeCN) followedby 300 mL (75% Et₂O: 25% MeCN) and (50% Et₂O: 50% MeCN) until elution.The concentrated product was suspended in 5 mL of MeCN and heated to 80°C. The solution was cooled to room temperature with stirring. Theproduct was precipitated with a slow dropwise addition of 50 mL of Et₂O.The crystals were collected and the same precipitation was performed asecond time to afford 4-trifluoromethyl-2-pyridyl MIDA boronate as anoff-white crystalline solid (1.35 g, 53%). ¹H-NMR (500 MHz, CD₃CN) δ8.92 (d, J=5 Hz, 1H), 7.86 (s, 1H), 7.57 (d, J=5 Hz, 1H), 4.13 (d, J=17Hz, 2H), 4.00 (d, J=17 Hz, 2H), 2.56 (s, 3H).

To form protected organoboronic acid 6-bromo-2-pyridyl MIDA boronate 21,the general procedure was followed using 2,6-dibromopyridine (2.04 g,8.6 mmol), triisopropyl borate (2 mL, 8.6 mmol), THF (26 mL), DMSO (17mL), nBuLi (3.44 mL, 2.5 M in hexanes), and N-methyliminodiacetic acid(2.15 g, 14.62 mmol). The mixture was eluted using a hexanes and ethylacetate gradient (25% hexanes: 75% EtOAc→100% EtOAc). The concentratedproduct was suspended in 17 mL of acetone and was precipitated with aslow dropwise addition of 170 mL of hexanes. The crystals were collectedto afford 6-bromo-2-pyridyl MIDA boronate as a white crystalline solid(1.46 g, 54%). ¹H-NMR (400 MHz, CD₃CN) δ 7.62 (dt, J=3.2, 6 Hz, 2H),7.49 (dt, J=3.2, 11.5 Hz, 1H), 4.10 (d, J=16.8 Hz, 2H), 3.96 (d, J=16.8Hz, 2H), 2.58 (s, 3H).

To form protected organoboronic acid 2-pyrazinyl MIDA boronate 5a, thegeneral procedure was followed using 2-bromo pyrazine (275 μL, 3.0mmol), triisopropyl borate (690 μL, 3.0 mmol), THF (11 mL), DMSO (6 mL),nBuLi (1.2 mL, 2.5 M in hexanes), and N-methyliminodiacetic acid (750mg, 5.1 mmol). The mixture was eluted using 300 mL (95% Et₂O: 5% MeCN)followed by 100% MeCN until elution of product. The appropriatefractions were concentrated, azeotroped with DCM three times and placedunder high vacuum for 20 minutes to afford 2-pyrazinyl MIDA boronate asan orange crystalline solid (300 mg, 43%). ¹H-NMR (500 MHz, CD₃CN) δ8.77 (d, J=1.5 Hz, 1H), 8.70 (t, J=1.5 Hz 1H), 8.53 (d, J=2.5 Hz, 1H),4.13 (d, J=17 Hz, 2H), 3.98 (d, J=17 Hz, 2H), 2.59 (s, 3H).

To form protected organoboronic acid 5-thiazolyl MIDA boronate 5e, thegeneral procedure was followed using 5-bromothiazole (760 μL, 8.6 mmol),triisopropyl borate (2 mL, 8.6 mmol), THF (26 mL), DMSO (17 mL), nBuLi(3.44 mL, 2.5 M in hexanes), and N-methyliminodiacetic acid (2.15 g,14.62 mmol). The mixture was eluted using an ether and acetonitrilegradient. The appropriate fractions were concentrated. The mixture wasthen suspended in 5 mL of acetonitrile and heated to 80° C. withstirring and then cooled to room temperature. The mixture was dilutedwith 20 mL of DCM then with stirring 60 mL of Ether was added dropwiseover 1 hour. The off-white crystalline solid was filtered then washedthrough the frit into a clean round bottom flask. The resulting solutionwas concentrated then azeotroped three times with a 50:50 Ether:DCMmixture. The resulting crystalline solid was placed under a high vacuumfor 20 minutes to afford 5-thiazolyl MIDA boronate 5e as an off-whitecrystalline solid (337 mg, 44%). ¹H-NMR (500 MHz, CD₃CN) δ 9.03 (s, 1H),7.98 (s, 1H), 4.10 (d, J=17 Hz, 2H), 3.93 (d, J=17 Hz, 2H), 3.73 (s,3H). ¹³C-NMR (125 MHz, CD₃CN) δ 168.8, 158.1, 150.0, 62.6, 48.5.

Example 2 Preparation of Ethynyl MIDA Boronate from CorrespondingGrignard Reagent

To an oven-dried 5000-mL 3-neck round-bottomed flask equipped with amagnetic stir bar, a 500-mL pressure-equalizing addition funnel, and tworubber septa was added THF (750 mL) and trimethyl borate (61 mL, 550mmol, 1.1 equiv) under an atmosphere of Ar(g). The solution was cooledto 78° C. in a dry ice/IPA bath. The addition funnel was charged withthe first portion of ethynal magnesium bromide solution (500 mL, 250mmol, 0.50 M in THF) and added drop-wise over 35 min. The additionfunnel was charged with the second portion of ethynal magnesium bromidesolution (500 mL, 250 mmol, 0.50 M in THF) and added drop-wise over 30min. The reaction vessel was removed from the bath and allowed to warmto ambient temperature over the course of 3 h resulting in a thick whiteslurry. While the slurry of the “ate” complex was warming to ambienttemperature, an oven-dried 3000-mL 3-neck round-bottomed flask equippedwith a magnetic stir bar, a thermometer, a septum, and a distillationtrain was charged with MIDA (162 g, 1100 mmol, 2.2 equiv), DMSO (750 mL)and toluene (300 mL). Using a heating mantle and variac, the suspensionwas brought to an internal temp of 120° C. and the H₂O/toluene azeotropedistilled off (head temperature of 82-87° C.) resulting in a homogeneouslight-orange solution. The internal temperature of the solution wasraised to 140° C. and the suspension of the “ate” complex was added overthe course of 4 h via cannula transfer (Teflon® cannula, innerdiameter=4 mm) under a positive pressure of Ar(g) at a rate such thatthe internal temperature remained between 120-160° C.

After the addition was completed the reaction vessel was washed with THF(2×60 mL) and the washes added via cannula transfer to the reactionvessel containing the MIDA solution. The remaining THF and MeOH wereallowed to distill off (˜15 min) followed by vacuum distillation of theDMSO. The reaction vessel was allowed to cool to ambient temperature andacetone was added (1.5 L) with manual and mechanical agitation.Overnight agitation of this mixture resulted in a thick brown slurrythat was filtered and the collected brown solids were washed withacetone (3×300 mL). The filtrate was concentrated under reduced pressureto afford a thick black oil that was cooled to 0° C. in an ice-bath andtreated with brine (500 mL) for 30 min with vigorous stirring. Theresulting brown precipitate was collected by suction filtrationaffording the crude MIDA boronate. Semi-purification by chromatographyfollowed by treatment of the crude MIDA boronate with charcoal inacetone provided a yellow oil after concentration under reducedpressure. The crude oil was dissolved in a minimal amount of acetone andEt₂O was added to precipitate the MIDA boronate 7a as a white solid thatwas collected by suction filtration and washed with Et₂O (crop 1=41.0 g,crop 2=4.5 g) to provide the title compound as an off white powder in50% yield.

Example 3 Preparation of Propynyl MIDA Boronate from CorrespondingGrignard Reagent

To a 300 mL 3-neck round bottom flask equipped with a stir bar was addedB(OMe)₃ (5.9 mL, 53 mmol) and THF (50 mL). The solution was cooled to−78° C. Propynylmagnesium bromide (0.5 M in THF, 100 mL, 50 mmol) wasadded dropwise via cannula over 45 min. The resulting solution wasstirred at −78° C. for 1.5 hr, followed by stirring at 23° C. for 2 hr.In a separate 500 mL 3-neck round bottom flask equipped with a stir bar,internal thermometer, 500 mL addition funnel, and distillation apparatuswas added MIDA (15.0 g, 102 mmol) and DMSO (50 mL). The solution washeated with an oil bath to an internal temperature of 110-115° C. Theborate suspension was transferred to the addition funnel and wascontinuously agitated with a stream of nitrogen. The borate solution wasadded dropwise to the hot MIDA solution over 2 hr 50 min, keeping theinternal temperature between 105 and 115° C.

After full addition of the borate solution, the reaction solution wascooled to 60° C. and placed under vacuum (300 mtorr) to distill thereaction to dryness. The resulting foam was cooled to room temperatureand dissolved in 200 mL EtOAc, 50 mL acetone, and 75 mL H₂O and pouredinto 200 mL EtOAc:Acetone (1:1) and 75 mL brine. The mixture was shakenand the aqueous layer was removed and extracted with EtOAc (1×100 mL).The combined organic phases were washed with brine (2×20 mL). The brinewash was back extracted with EtOAc:Acetone (2:1, 1×75 mL) The combinedorganic phases were dried over MgSO₄, filtered, and concentrated invacuo. The resulting yellow solid was dissolved in 100 mL THF and 1000mL Et₂O was added to precipitate the product. The resulting solid wascollected by vacuum filtration to yield propynyl MIDA boronate 7b as awhite solid (7.48 g, 77%).

Example 4 Preparation of Vinyl MIDA Boronate from Corresponding GrignardReagent

To a dry 500 mL Schlenk flask equipped with a stir bar was added THF(100 mL) and B(OMe)3 (11.7 mL, 105 mmol). The solution was cooled via a−78° C. cold bath. To the solution was added via cannula over 5 min.vinylmagnesium bromide as a solution in THF (1.0 M, 100 mL, 100 mmol).The resulting mixture was stirred for 2 h, then the cold bath wasremoved and the mixture was allowed to warm to room temperature withstirring for 2 h. The beige mixture was transferred to a 250 mLpressure-equalizing addition funnel. A 3-neck 500 mL round bottom flaskequipped with a stir bar was charged with DMSO (100 mL),N-methyliminodiacetic acid (29.5 g, 200 mmol) and toluene (50 mL). Tothe necks of the round bottom were fitted the addition funnel, athermometer, and a std. distillation apparatus. The mixture was heatedto an internal temperature of 115° C. upon which the THF mixture wasadded via the addition funnel at a rate to maintain an internaltemperature between 95-110° C. During this time the THF is distilledaway from the hot DMSO mixture. Upon completion of the addition andafter the internal temperature had risen to 120° C. the distillation potwas allowed to cool to room temperature.

The DMSO mixture was diluted with acetone (300 mL) and the resultingmixture was filtered through a pad of Celite. The collected solids wereextracted with acetone (100 mL) and the combined filtrate wasconcentrated in vacuo to afford a DMSO solution. The DMSO solution wasdistilled to near dryness (1 Torr, 100° C.). The remaining solids weredissolved in acetone:water (100 mL:100 mL) and were transferred to a1000 mL separatory funnel. The solution was diluted with brine (100 mL)and EtOAc (200 mL). The mixture was shaken and the phases wereseparated. The aq. phase was twice extracted with acetone:EtOAc (100mL:200 mL). The combined organics were washed with brine (3×100 mL). Thecombined brine washes were back-extracted with EtOAc (100 mL). Thecombined organics were dried over MgSO4, filtered, then concentrated invacuo to afford an off-white solid which was then recrystallized fromacetone (100 mL) diluted with Et2O (2000 mL) to afford the product 7c asan off-white solid (9.95 g, 54%).

Example 5 Preparation of Propynyl MIDA Boronate by Direct Deprotonation

To a dry 50 mL graduated Schlenk tube cooled in a −78° C. bath was addedin small portions 1-butyne gas until 12 mL of 1-butyne (150 mmol) hadcondensed in the flask. Separately, a dry 200 mL Schlenk flask equippedwith a stir bar was charged with THF (100 mL) and n-BuLi (2.5 M inhexanes, 40 mL, 100 mmol), and then cooled via a −78° C. bath. To then-BuLi solution was added in small portion the liquid butyne at a ratenecessary to keep the internal temperature below −45° C. Following theaddition, the solution was stirred for 1 h at an internal temp of −65°C. Separately, a dry 500 mL 3-neck flask equipped with a stir bar wascharged with THF (50 mL) and B(OMe)₃ (11.1 mL, 100 mmol), then cooled toan internal temp of −65° C. To the B(OMe)₃ solution was added viacannula the alkyne solution. Following the addition, the solution wasallowed to warm to room temperature with stirring over 2 h. Separately,a 300 mL 3-neck flask equipped with a large stir bar was charged withDMSO (100 mL) and N-methyliminodiacetic acid (23.87 g, 160 mmol). Theflask was fitted with a thermometer and a standard distillationapparatus. The DMSO mixture was heated to an internal temperature of110° C., upon which to the mixture was added via cannula the boratesolution at a rate necessary to maintain an internal temperature of95-115° C.

Following the addition, residual THF was distilled at 30 Torr, then DMSOwas reduced to a minimum via distillation at 1 Torr. The resultingmixture was transferred to a 1000 mL separatory funnel using acetone(100 mL) and water (100 mL). The mixture was diluted with brine (100mL), then extracted with EtOAc (200 mL). The aq. phase was extractedwith acetone:EtOAc (100 mL:200 mL). The combined organics were washedwith water (2×200 mL), then brine (2×50 mL). The combined aqueous washeswere back-extracted with EtOAc (3×100 mL). The combined organics weredried over MgSO₄, filtered, and then concentrated in vacuo. The productwas recrystallized by dissolving the residue in a minimum volume ofacetone and then layering the solution with Et₂O (1.5 L) and allowing tostand for 24 h. The resulting crystals were collected via filtration toafford the pure product as a colorless, crystalline solid, 4.05 g (19%).¹H-NMR (acetone-d6, 500 MHz): 4.23 (d, J=17.0 Hz, 2H), 4.05 (d, J=17 Hz,2H), 3.19 (s, 3H), 2.21 (q, J=7.5 Hz, 2H), 1.11 (t, J=7.5 Hz, 3H).

Example 6 Preparation of MIDA Anhydride

A round-bottom flask equipped with a PTFE-coated magnetic stir bar wascharged with N-methyliminodiacetic acid (25.0 g, 170 mmol, 1.0 equiv),acetic anhydride (85 mL, ˜850 mmol, ˜5 equiv.), and pyridine (274.9 μL,3.4 mmol, 0.02 equiv). The flask was capped with a rubber septum whichwas pierced with an 18 gauge needle (alternatively a reflux condensercould be used). The reaction was lowered into a preheated 70° C. oilbath and stirred until the mixture became clear and dark orange (about1.5 h). The acetic acid, pyridine, and remaining acetic anhydride werethen removed by vacuum distillation (37° C. to 42° C. at 30 Torr). Theresulting brown-black liquid was azeotroped three times with toluene (50mL) to remove residual acetic acid and then transferred to an Erlenmeyerflask. To this flask was added enough diethyl ether to dissolve thecrude N-methyl morpholine dione product (˜400 mL). The resulting mixturewas filtered to remove a black-brown precipitate, and the filtrate wasconcentrated in vacuo. The resulting pale yellow solid was thenrecrystallized from a minimum amount of hot diethyl ether to yieldN-methyl morpholine dione (MIDA anhydride; 16.9 g, 131 mmol, 77%) as anoff-white crystalline solid.

Example 7 Preparation of Protected Organoboronic Acids fromCorresponding Boronic Acids Using MIDA Anhydride

The general method for synthesizing protected organoboronic acids was asfollows. A flame-dried 20 mL i-chem vial equipped with a PTFE-coatedmagnetic stir bar was charged with boronic acid (1 mmol, 1 equiv.) andMIDA anhydride (2.5-5 mmol, 2.5-5 equiv.). The vial was capped with aPTFE-lined septum cap, evacuated and backfilled with argon three times.To this vial was added 5 mL dry THF through syringe. The vial waslowered into a pre-heated 70° C. aluminum heat block, where the reactionstirred for 14-24 h. The vial was then removed from the heating sourceand allowed to cool to room temperature. The solution was transferred toa 125 mL separatory funnel with 5 mL diethyl ether followed by 15 mLdeionized water. The phases are separated and the aqueous layer isextracted four times with 15 mL 1:1 diethyl ether:THF. The combinedorganics are washed with 30 mL saturated NaCl, dried over magnesiumsulfate, and concentrated in vacuo.

To form protected organoboronic acid chlormethyl MIDA boronate 11b, thegeneral procedure was followed. To a 7 mL vial equipped with a stir barwas added chloromethylboronic acid (102.5 mg, 1.1 mmol, 1.0 eq), MIDAanhydride (345.4 mg, 2.7 mmol, 2.5 eq), and dry THF (2 mL, 0.5 M). Thevial was flushed with nitrogen and the sealed vial was placed in a 70°C. heating block. After 30 min. the reaction solution was cooled to roomtemperature and filtered through a plug of celite, eluting with acetone.The solution was concentrated in vacuo. The residue was dissolved inacetone and precipitated from solution with Et₂O. The white solid wascollected by vacuum filtration to afford chloromethyl MIDA boronate(140.5 mg, 63%).

While various embodiments of the invention have been described, it willbe apparent to those of ordinary skill in the art that other embodimentsand implementations are possible within the scope of the invention.Accordingly, the invention is not to be restricted except in light ofthe attached claims and their equivalents.

Example 8 Preparation of Iodopolyenyl MIDA Boronates

This example presents a strategy for preparing iodopolyenyl MIDAboronates via the iterative cross coupling (ICC) of iodo-maskedbifunctional building blocks. As shown in FIG. 9, the approach involvesmetal-selective cross-coupling of Sn/Ge bis-metallated olefins togenerate polyenylgermanium intermediates followed by stereospecificiododegermylations. To the best of our knowledge, iododegermylations ofpolyenylgermanium species were unreported. We hypothesized thatiterative cycles of metal-selective coupling/iododegermylation with corebuilding blocks 1 and 2 (FIG. 9B) could provide access to iodo-polyenylMIDA boronates in all possible stereoisomeric forms (FIG. 9C).

We discovered that (E)-1 and (Z)-1 can both be generated from ethynylMIDA boronate 6, which in turn can be prepared from readily-availableGrignard reagent 5. Specifically, as shown in FIG. 10, the addition of 5to trimethyl borate followed by direct transligation of the resultingmagnesium ate complex with MIDA generated 6 as a colorless, crystallinesolid. When this transligation was executed at 115° C., a good yield of6 was achieved on the decagram scale. Although 6 is fully compatiblewith silica gel chromatography, this highly versatile building block canalso be conveniently isolated in excellent purity via recrystallization.One-pot hydrostannylation of 6 followed by iododestannylation of theresulting bis-metallated intermediate provided an excellent yield of(E)-1. Alternatively subjecting 6 to a series of silver-promoted alkyneiodination followed by PADC-mediated semireduction provided thecomplementary building block (Z)-1. Importantly, both (E)-1 and (Z)-1are air- and chromatographically-stable, highly crystalline free-flowingsolids.

A synthesis of (E)-2 has been previously reported, but astereocontrolled route to (Z)-2 was unknown. (F. David-Quillot, J.Thibonnet, D. Marsacq, M. Abarbri, A. Duchene, Tetrahedron Lett. 2000,41, 9981-9984) As shown in FIG. 11, hybridizing methodology previouslyreported for the germyl-stannylation of substituted alkynes and thesilyl-stannylation of acetylene core building block (Z)-2 wasefficiently prepared as a single stereoisomer via the palladium-mediatedcis-germyl-stannylation of acetylene gas.

With these four core building blocks in hand, we sought generalconditions for efficient cycles of stereospecific metal-selectivecouplings and iododegermylations (FIG. 9A). As shown in FIG. 12, wefound that Liebeskind-type conditions are remarkably effective for thetargeted metal-selective Stille couplings. In fact, using the exact sameset of very mild conditions [Pd(PPh)₄/CuTC, DMF, 0° C. to 23° C.], allpossible combinations of 1 and 2 were stereospecifically coupled inexcellent yields to generate dienylgermanium intermediates 8. Completingthe envisioned cycle, stereospecific iododegermylations of all four ofthese intermediates were readily achieved via treatment with I₂ in MeOHat −78° C., thereby providing all of the targeted iododienyl MIDAboronate building blocks 3 in good yields and as single stereoisomers.Harnessing the iterative nature of this strategy, the more advancedtrienyl halide, (E,E,E)-4 was also readily prepared via simply executingan additional cycle of metal-selective coupling and stereospecificiododegermylation (FIG. 13).

As shown in Table 1 below, these bifunctional building blockscollectively enable the preparation of a broad range of stereochemicallycomplex polyene natural product frameworks. After surveying a variety ofcatalysts, bases, and solvents we found a very mild set of Buchwald-typecross-coupling conditions [Pd(OAc)₂, SPhos or XPhos, Cs₂CO₃, THF, 23°C.] that proved to be highly effective. Specifically, all possiblestereoisomers of 1 and 3 were cross-coupled with both (E)- and(Z)-pentenyl boronic acid 10 in good to excellent yields and withoutstanding levels of stereoretention. Observations of completestereoretention even when coupling the sterically encumbered MIDAboronate (Z)-1 (entries 2 and 8) and preparing the very challenging(Z,Z,Z)-triene 22 (entry 10) are particularly notable. Collectively,products 11-22 represent all possible stereoisomers of the core dienyl-and trienyl substructures that appear in a wide range of naturalproducts derived from all major biosynthetic pathways. Importantly,these products all retain the potential for subsequent cross-couplingreactions upon hydrolysis of the MIDA boronate functional group withmild, aqueous base.

TABLE 1 ^(a)Stereospecific Suzuki-Miyaura Cross-Couplings yielding allpossible stereoisomers of di- and trienyl MIDA boronates. iodoalkenylentry boronic Acid MIDA boronate product % yield 1

(E)-10 (E)-1

95 11 2 (E)-10 (Z)-1

77 12 3 (E)-10 (E,E)-3

75 13 4 (E)-10 (E,Z)-3

78 14 5 (E)-10 (Z,E)-3

87 15 6 (E)-10 (Z,Z)-3

64 16 7

(Z)-10 (E)-1

17 91 8 (Z)-10 (Z)-1

74 18 9 (Z)-10 (E,E)-3

77 19 10 (Z)-10 (E,Z)-3

84 20 11 (Z)-10 (Z,E)-3

82 21 12 (Z)-10 (Z,Z)-3

62 22 ^(a)1.0 equiv. 1 or 3, 1.5 equiv. 10, Pd(OAc)₂, SPhos (entries 1,3, 4, 7, 9, 10) or XPhos (entries 2, 5, 6, 8, 11, 12), Cs₂CO₃, THF, 23°C.

Example 9 Preparation of Propynyl MIDA Boronate

To a 300 mL 3-neck round bottom flask equipped with a stir bar was addedB(OMe)₃ (5.9 mL, 53 mmol) and THF (50 mL). The solution was cooled to−78° C. Propynylmagnesium bromide (0.5 M in THF, 100 mL, 50 mmol) wasadded dropwise via cannula over 45 min. The resulting solution wasstirred at −78° C. for 1.5 hr, followed by stirring at 23° C. for 2 hr.In a separate 500 mL 3-neck round bottom flask equipped with a stir bar,internal thermometer, 500 mL addition funnel, and distillation apparatuswas added MIDA (15.0 g, 102 mmol) and DMSO (50 mL). The solution washeated with an oil bath to an internal temperature of 110-115° C. Theborate suspension was transferred to the addition funnel and wascontinuously agitated with a stream of nitrogen. The borate suspensionwas added dropwise to the hot MIDA solution over 2 hr 50 min, keepingthe internal temperature between 105 and 115° C. After full addition ofthe borate suspension, the reaction solution was cooled to 60° C. andplaced under vacuum (300 mTorr) to distill the reaction to dryness. Theresulting foam was cooled to 23° C. and dissolved in 200 mL EtOAc, 50 mLacetone, and 75 mL H₂O and poured into 200 mL EtOAc:Acetone (1:1) and 75mL brine. The mixture was shaken and the aqueous layer was removed andextracted with EtOAc (1×100 mL). The combined organic phases were washedwith brine (2×20 mL). The brine wash was back extracted withEtOAc:Acetone (2:1, 1×75 mL) The combined organic phases were dried overMgSO₄, filtered, and concentrated in vacuo. The resulting yellow solidwas dissolved in 100 mL THF and 1000 mL Et₂O was added to precipitatethe product. The resulting solid was collected by vacuum filtration toyield propynyl MIDA boronate as a white solid (7.48 g, 77%). TLC(Et₂O:Acetone 2:1): R_(f)=0.28, stained by KMnO₄. ¹H-NMR (500 MHz,d₆-acetone): δ 4.22 (d, J=17 Hz, 2H), 4.05 (d, J=17 Hz, 2H), 3.18 (s,3H), 1.83 (s, 3H). ¹³C-NMR (125 MHz, d₆-acetone): δ 168.6, 62.1, 48.2,41.1, 4.0. ¹¹B-NMR (96 MHz, d₆-acetone): δ 6.8. HRMS (ESI+): Calculatedfor C₈H_(1l)BNO₄: 196.0781; Found: 196.0784. IR (thin film, cm⁻¹): 3009,2957, 2203, 1790, 1462, 1342, 1290, 1260, 1192, 1169, 1092, 994, 882,858, 706.

Example 10 Synthesis of Isoprenyl MIDA boronate

To a 500 mL 3-neck round bottom flask equipped with a stir bar was addedB(OMe)₃ (12.0 mL, 105 mmol) and THF (100 mL). The solution was cooled to−78° C. Isoprenylmagnesium bromide (0.5 M in THF, 200 mL, 100 mmol) wasadded dropwise via cannula over 2 hr. The resulting solution was stirredat −78° C. for 1.5 hr, followed by stirring at 23° C. for 2 hr. To aseparate 1000 mL 3-neck round bottom flask equipped with a stir bar,internal thermometer, 500 mL addition funnel, and distillation apparatuswas added MIDA (29.9 g, 203 mmol) and DMSO (100 mL). The solution washeated with an oil bath to an internal temperature of 110-115° C. Theborate suspension was transferred to the addition funnel and wascontinuously agitated with a stream of nitrogen. The borate suspensionwas added dropwise to the hot MIDA solution over 2 hr, keeping theinternal temperature between 100 and 115° C. After full addition of theborate suspension, the reaction solution was cooled to 60° C. and placedunder vacuum (250 mTorr) to distill the reaction to dryness. Theresulting foam was cooled to 23° C. and dissolved in 400 mL EtOAc and150 mL H₂O and poured into 400 mL EtOAc:Acetone (1:1) and 150 mL brine.The mixture was shaken and the aqueous layer was removed and extractedwith EtOAc (2×200 mL). The combined organic phases were washed withbrine (2×20 mL). The brine wash was back extracted with EtOAc:Acetone(2:1, 1×75 mL) The combined organic phases were dried over MgSO₄,filtered, and concentrated in vacuo. The resulting white solid wassuspended in 150 mL THF and 1500 mL of Et₂O was added to precipitate theproduct. The resulting solid was collected by vacuum filtration to yieldisoprenyl MIDA boronate as a white solid (15.91 g, 81%). TLC (Et₂O:MeCN4:1): R_(f)=0.43, stained by KMnO₄. ¹H-NMR (500 MHz, d₆-acetone): δ 5.45(bs, 1H), 5.32 (d, J=2.5 Hz, 1H), 4.21 (d, J=17 Hz, 2H), 4.03 (d, J=17Hz, 2H), 3.00 (s, 3H), 1.78 (s, 3H). ¹³C-NMR (100 MHz, d₆-acetone): δ169.1, 124.4, 62.5, 47.0, 22.0. ¹¹B-NMR (128 MHz, d₆-acetone): 11.2.

Example 11 Large Scale Preparation of 1-Ethynylboronate Ester

To maximize the yield for this reaction, the MIDA ligand was purifiedand dried as follows: MIDA was dissolved in a minimum volume ofdeionized water. Using a mechanical stirrer and a large separatoryfunnel, the MIDA was precipitated through the dropwise addition ofacetone (5× volume relative to water used to dissolve MIDA). Theresulting slurry was filtered and the collected white solid was washedwith small portions of acetone. This solid was then transferred to arecrystallization dish and placed in a 60° C. oven for 12 h. Theresulting solid was ground in a mortar and then placed into a 120° C.oven for four hours. The results are comparable or improved if the MIDAis dried overnight in a vacuum oven.

To an oven-dried 5000-mL 3-neck round-bottomed flask equipped with amagnetic stir bar, a 500-mL pressure-equalizing addition funnel, and tworubber septa was added THF (750 mL) and trimethyl borate (61 mL, 550mmol, 1.1 equiv) and the resulting solution was cooled to −78° C. Theaddition funnel was charged with the first portion of ethynyl magnesiumbromide solution (500 mL, 250 mmol, 0.50 M in THF) which was then addeddrop-wise over 35 min. The addition funnel was charged with the secondportion of ethynyl magnesium bromide solution (500 mL, 250 mmol, 0.50 Min THF) which was then added drop-wise over 30 min. The reaction vesselwas removed from the bath and allowed to warm to ambient temperatureover the course of 3 h resulting in a thick white slurry. A separateoven-dried 3000-mL 3-neck round-bottomed flask equipped with a magneticstir bar, a thermometer, 500 mL addition funnel, and a distillationtrain was charged with MIDA (162 g, 1100 mmol, 2.2 equiv) and DMSO (750mL). Using a heating mantle and variac, the suspension was brought to aninternal temp of 130° C. To the addition funnel was added 500 mL ofhexanes which was then added drop-wise to the MIDA solution (this stepwas included to azeotropically dry the MIDA solution, head temperatureof 60-69° C.) resulting in a homogeneous light-orange solution. Thepreviously prepared suspension of the “ate” complex was added over thecourse of 1.5 h via cannula transfer under a positive pressure of Ar(g)at a rate such that the internal temperature remained between 120-160°C. After the addition was completed the reaction vessel was washed withTHF (2×60 mL) and the washes added via cannula transfer to the reactionvessel containing the MIDA solution. The remaining THF and MeOH wereallowed to distill off (˜15 min). The reaction vessel was allowed tocool to ambient temperature. The reaction mixture was then transferredto a 6 L separatory funnel. To this was added 1 L of de-ionized water, 1L of brine, 1.5 L of ethyl acetate, and 1 L of acetone. The organiclayer was separated, and the aqueous layer was extracted twice with 500mL of a 3:2 ethyl acetate: acetone solution and once with 500 mL ofethyl acetate. The combined organic fractions were then washed with 500mL of brine, and dried with MgSO₄. The organic fractions were thenconcentrated to form a light brown solid. The solid was dissolved in 250mL of acetone and then was precipitated by the drop-wise addition of 3 Lof diethyl ether. The resulting solid was collected via filtration andwashed with diethyl ether (2×50 mL). The solid was dissolved using 800mL of acetone. To this solution was added activated charcoal. This wasstirred for 30 min, and then filtered through celite washing withacetone (2×50 mL). The resulting solution was concentrated in vacuo toafford ethynyl MIDA boronate (66.6 g, 74%).

This compound was stable to long-term storage in a vial on the benchtopunder air in a subdued light environment (as judged by the ¹H NMRspectrum acquired after 6 months of storage). TLC (EtOAc) R_(f)=0.46,visualized with KMnO₄. ¹H NMR (400 MHz, CD₃CN): δ 4.00 (d, J=17.2 Hz,2H), 3.87 (d, J=17.2 Hz, 2H), 3.03 (s, 3H), 2.69 (s, 1H). ¹³C NMR (100MHz, CD₃CN): δ 168.5, 90.1 (br), 62.2, 48.6. HRMS (ESI): Calculated forC₇H₉BNO₄ (M+H)⁺: 182.0625; Found: 182.0623.

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. published patent applications citedherein are hereby incorporated by reference.

EQUIVALENTS

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. Therefore, the foregoing embodiments are presented by way ofexample only and, within the scope of the appended claims andequivalents thereto, the invention may be practiced otherwise than asspecifically described.

1. A method of forming a protected boronic acid, comprising: reacting ina reaction mixture an imino-di-carboxylic acid, and an organoboronatesalt represented by formula (I):[R¹—B(OR²)(OR³)(OR⁴)]⁻M⁺  (I); wherein R¹ is an organic group, R², R³and R⁴ independently are selected from the group consisting of an alkylgroup and an aryl group, and M⁺ is selected from the group consisting ofa metal ion, a metal halide ion and an ammonium ion; and the reactionmixture further comprises a polar aprotic solvent; wherein the reactingcomprises maintaining the reaction mixture at a temperature of at least100° C.; and thereby forming a protected organoboronic acid representedby formula (III) in the reaction mixture:

wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently are selected from thegroup consisting of a hydrogen group and an organic group.
 2. The methodof claim 1, wherein R¹ is an alkyl group, a heteroalkyl group, analkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynylgroup, an aryl group, a heteroaryl group, or a combination of at leasttwo of these groups.
 3. The method of claim 1, wherein R¹ is representedby formula (IV):Y—R⁵—(R⁶)_(m)—  (IV), wherein Y is a halogen group or a pseudohalogengroup; R⁵ is an aryl group or a heteroaryl group; R⁶ is an alkyl group,a heteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynylgroup, a heteroalkynyl group, an aryl group, a heteroaryl group, or acombination of at least two of these groups; and m is 0 or
 1. 4. Themethod of claim 3, wherein R⁵ is a heteroaryl group.
 5. The method ofclaim 1, wherein R¹ is a heterocyclic group, an alkynyl group or analkenyl group.
 6. The method of claim 5, wherein said heterocyclic groupis selected from the group consisting of pyridine, indole, isoindole,indazole, purine, indolizidine, quinoline, isoquinoline, quinazoline,pteridine, quinolizidine, pyrrole, pyrazine, pyridazine, pyrimidine,imidazole, pyrasole, isoxazole, oxazole, thiazole, benzthiazole, furan,benzofuran, thiophene and benzothiophene.
 7. The method of claim 1,wherein R¹ is a 2-heterocyclic group selected from the group consistingof 2-pyridyl, 2-indolyl, 2-isoindolyl, 2-indazolyl, 2-purinyl,2-indolizidinyl, 2-quinolinyl, 2-isoquinolinyl, 2-quinazolinyl,2-pteridinyl, 2-quinolizidinyl, 2-pyrrolyl, 2-pyrazinyl, 2-pyridazinyl,2-pyrimidinyl, 2-imidazolyl, 2-pyrasolyl, 2-isoxazolyl, 2-oxazolyl,2-thiazolyl, 2-benzthiazolyl, 2-furyl, 2-benzofuryl, 2-thiophenyl, and2-benzthiophenyl.
 8. The method of claim 1, wherein R², R³ and R⁴ areeach independently an alkyl group containing from 1 to 4 carbon atoms.9. The method of claim 8, wherein said alkyl group is methyl (—CH₃) orisopropyl (—CH(CH₃)₂).
 10. The method of claim 1, wherein M⁺ is selectedfrom the group consisting of Li⁺, Na⁺, K⁺, MgX⁺, CaX⁺, Zn⁺, Bu₄N⁺, andMe₄N⁺; and X is F, Cl, Br or I.
 11. The method of claim 10, wherein M⁺is Li⁺ or MgX⁺.
 12. The method of claim 1, wherein R¹⁰ is methyl, andeach of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen.
 13. The method of claim 1,wherein the polar aprotic solvent is selected from the group consistingof tetrahydrofuran (THF), dioxane, dimethyl formamide (DMF), dimethylsulfoxide (DMSO), toluene and xylene.
 14. The method of claim 1, whereinthe polar aprotic solvent is DMSO.
 15. The method of claim 1, whereinthe reaction mixture is at a temperature of from 100° C. to 200° C. 16.The method of claim 1, further comprising: reacting in a reactionmixture an organohalide or an organo-pseudohalide organolithium reagent(V), and a boronate ester, to form the organoboronate salt (VI)represented by the following reaction scheme:


17. The method of claim 1, further comprising: reacting in a reactionmixture an organic compound (VII), and a first organolithium reagent toform a second organolithium reagent (VIII); and reacting in a reactionmixture said second organolithium reagent (VIII), and a boronate esterto form a organoboronate salt (VI) represented by the following reactionscheme:

wherein R⁷ is a hydrocarbon group.
 18. The method of claim 1, furthercomprising: reacting in a reaction mixture an organic compound (VII),and Mg/Li 2,2,6,6-tetramethylpiperidyl amide to form a Grignard reagent(IX); and reacting in a reaction mixture said Grignard reagent (IX) anda boronate ester to form a organoboronate salt (X) represented by thefollowing reaction scheme:


19. A method of forming a protected boronic acid, comprising: reactingin a reaction mixture a N-substituted morpholine dione, and anorganoboronic acid represented by formula (XII):R¹—B(OH)₂  (XII), wherein R¹ is an organic group, and the reactionmixture further comprises a polar aprotic solvent; and thereby forming aprotected organoboronic acid represented by formula (III) in thereaction mixture:

where R¹⁰ represents an organic group, and R¹¹, R¹², R¹³ and R¹⁴independently are selected from the group consisting of a hydrogen groupand an organic group.
 20. The method of claim 19, wherein R¹ is an alkylgroup, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, analkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group,or a combination of at least two of these groups.
 21. The method ofclaim 19, wherein R¹ is represented by formula (IV):Y—R⁵—(R⁶)_(m)—  (IV), wherein Y is a halogen group or a pseudohalogengroup; R⁵ is an aryl group or a heteroaryl group; R⁶ is an alkyl group,a heteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynylgroup, a heteroalkynyl group, an aryl group, a heteroaryl group, or acombination of at least two of these groups; and m is 0 or
 1. 22. Themethod of claim 21, wherein R⁵ is a heteroaryl group.
 23. The method ofclaim 19, wherein R¹ is a heterocyclic group, an alkynyl group or analkenyl group.
 24. The method of claim 23, wherein said heterocyclicgroup is selected from the group consisting of pyridine, indole,isoindole, indazole, purine, indolizidine, quinoline, isoquinoline,quinazoline, pteridine, quinolizidine, pyrrole, pyrazine, pyridazine,pyrimidine, imidazole, pyrasole, isoxazole, oxazole, thiazole,benzthiazole, furan, benzofuran, thiophene and benzothiophene.
 25. Themethod of claim 19, wherein R¹ is a 2-heterocyclic group selected fromthe group consisting of 2-pyridyl, 2-indolyl, 2-isoindolyl, 2-indazolyl,2-purinyl, 2-indolizidinyl, 2-quinolinyl, 2-isoquinolinyl,2-quinazolinyl, 2-pteridinyl, 2-quinolizidinyl, 2-pyrrolyl, 2-pyrazinyl,2-pyridazinyl, 2-pyrimidinyl, 2-imidazolyl, 2-pyrasolyl, 2-isoxazolyl,2-oxazolyl, 2-thiazolyl, 2-benzthiazolyl, 2-furyl, 2-benzofuryl,2-thiophenyl, and 2-benzthiophenyl.
 26. The method of claim 19, whereinR¹⁰ is methyl, and each of R¹¹, R¹², R¹³ and R¹⁴ is hydrogen.
 27. Themethod of claim 19, wherein the polar aprotic solvent is selected fromthe group consisting of tetrahydrofuran (THF), dioxane, acetonitrile,dimethyl formamide (DMF), toluene and xylene.
 28. The method of claim19, wherein the polar aprotic solvent is THF.
 29. The method of claim19, wherein the reaction mixture is maintained at a temperature of from40° C. to 100° C.